Use of ring-fused bicyclic pyridyl derivatives as fgfr4 inhibitors

ABSTRACT

The present invention relates to therapeutic uses of compounds of formula (I) or a pharmaceutically acceptable salt thereof

FIELD OF THE INVENTION

The invention provides the use of bicyclic pyridyl derivatives compoundsin methods of treating disease.

BACKGROUND OF THE INVENTION

Normal growth, as well as tissue repair and remodeling, require specificand delicate control of activating growth factors and their receptors.Fibroblast Growth Factors (FGFs) constitute a family of over twentystructurally related polypeptides that are developmentally regulated andexpressed in a wide variety of tissues. FGFs stimulate proliferation,cell migration and differentiation and play a major role in skeletal andlimb development, wound healing, tissue repair, hematopoiesis,angiogenesis, and tumorigenesis (reviewed in Ornitz, Novartis Found Symp232: 63-76; discussion 76-80, 272-82 (2001)).

The biological action of FGFs is mediated by specific cell surfacereceptors belonging to the Receptor Protein Tyrosine Kinase (RPTK)family of protein kinases. These proteins consist of an extracellularligand binding domain, a single transmembrane domain and anintracellular tyrosine kinase domain which undergoes phosphorylationupon binding of FGF. Four FGFRs have been identified to date: FGFR1(also called Flg, fms-like gene, flt-2, bFGFR, N-bFGFR or Cek1), FGFR2(also called Bek-Bacterial Expressed Kinase-, KGFR, Ksam, Ksaml andCek3), FGFR3 (also called Cek2) and FGFR4. All mature FGFRs share acommon structure consisting of an amino terminal signal peptide, threeextracellular immunoglobulin-like domains (Ig domain I, Ig domain II, Igdomain Ill), with an acidic region between Ig domains (the “acidic box”domain), a transmembrane domain, and intracellular kinase domains(Ullrich and Schlessinger, Cell 61: 203, 1990; Johnson and Williams(1992) Adv. Cancer Res. 60: 1-41). The distinct FGFR isoforms havedifferent binding affinities for the different FGF ligands.

Alterations in FGFRs have been associated with a number of human cancersincluding myeloma, breast, stomach, colon, bladder, pancreatic andhepatocellular carcinomas. Recently, it was reported that FGFR4 may playan important role in liver cancer in particular (PLoS One, 2012, volume7, 36713). Other studies have also implicated FGFR4 or its ligand FGF19in other cancer types including breast, glioblastoma, prostate,rhabdomyosarcoma, gastric, ovarian, lung, colon (Int. J. Cancer 1993;54:378-382; Oncogene 2010; 29:1543-1552; Cancer Res 2010; 70:802-812;Cancer Res 2011; 71:4550-4561; Clin Cancer Res 2004; 10:6169-6178;Cancer Res 2013; 73:2551-2562; Clin Cancer Res 2012; 18:3780-3790; J.Clin. Invest. 2009; 119:3395-3407; Ann Surg Oncol 2010; 17:3354-61;Cancer 2011; 117:5304-13; Clin Cancer Res 2013; 19:809-820; PNAS 2013;110:12426-12431; Oncogene 2008; 27:85-97).

Therapies involving FGFR4 blocking antibodies have been described forinstance in WO2009/009173, WO2007/136893, WO2012/138975, WO2010/026291,WO2008/052798 and WO2010/004204. WO2014/144737 and WO2014/011900 alsodescribe low molecular weight FGFR4 inhibitors.

Given the numerous therapies available to an individual having aparticular disease, a determination of the factors that influence, forexample, response to a particular drug, could be used to provide apatient with a personalized treatment regime. Such personalizedtreatment regimens offer the potential to maximize therapeutic benefitto the patient while minimizing related side effects that can beassociated with alternative and less effective treatment regimens.

SUMMARY OF THE INVENTION

The present invention aims to address the need for more adapted andeffective treatment regimens using FGFR4 inhibitors. The inventionprovides compounds, pharmaceutically acceptable salts thereof,pharmaceutical compositions thereof, which compounds are FGFR4inhibitors, for use in methods of treating, preventing, or amelioratingcancers.

In particular, the invention relates to methods of treating, preventingor ameliorating solid malignancies in a patient, wherein the solidmalignancies are characterized by positive expression of certainbiomarkers.

Various embodiments of the invention are described herein.

Within certain aspects, provided herein is a compound of formula (I) ora pharmaceutically acceptable salt thereof:

for use in the treatment of solid malignancies characterized by positiveFGFR4 and KLB expression, or positive FGFR4 and FGF19 expression, orpositive FGFR4, KLB and FGF19 expression.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides, in a first aspect, a compound of formula (I) ora pharmaceutically acceptable salt thereof

whereinV is selected from CH₂, O, CH(OH);W is selected from CH₂, CH₂CH₂, bond;

X is C(R^(X)) or N; Y is C(R^(Y)) or N; Z is CH or N;

wherein when X is N, Y and Z are not N;wherein when Y is N, X and Z are not N;wherein when Z is N, X and Y are not N;R^(X) is selected from hydrogen, halogen, haloC₁-C₃alkyl, cyano,C₁-C₆alkyl, hydroxyC₁-C₆alkyl;R^(Y) is selected from hydrogen, halogen, C₁-C₃alkyl, C₁-C₆alkoxy,hydroxyC₁-C₃alkoxy, NR^(Y1)R^(Y2), cyano, C₁-C₃alkoxyC₁-C₃alkoxy,C₁-C₃alkoxy-haloC₁-C₃alkoxy, di(C₁-C₃alkyl)aminoC₁-C₆alkoxy,O—(CH₂)₀₋₁—R^(Y3), CR^(Y6)R^(Y7), S—C₁-C₃alkyl, haloC₁-C₆alkoxyoptionally substituted with hydroxy;orR^(X) and R^(Y) together with the ring to which they are attached form abicyclic aromatic ring system optionally further comprising one or twoheteroatoms selected from N, O, or S, which ring system is optionallysubstituted with C₁-C₃alkyl;R^(Y1) is hydrogen andR^(Y2) is selected from C₁-C₆alkyl; hydroxyC₁-C₆alkyl; haloC₁-C₆alkyloptionally substituted with hydroxy; C₁-C₄alkoxyC₁-C₆alkyl;haloC₁-C₃alkoxyC₁-C₆alkyl; (CH₂)₀₋₁—R^(Y4);di(C₁-C₃alkyl)aminoC₁-C₆alkyl substituted with hydroxy;bicycloC₅-C₈alkyl optionally substituted with hydroxyC₁-C₃alkyl; phenylsubstituted with S(O)₂—CH(CH₃)₂; C₂-C₃alkylsulfonic acid;orR^(Y1) and R^(Y2) together with the N atom to which they are attachedform a saturated or unsaturated non-aromatic 6-membered heterocyclicring which may contain an O atom, which ring may be substituted once ortwice by R^(Y5);R^(Y3) is selected from quinuclidinyl, a 4-, 5- or 6-membered saturatedheterocyclic ring comprising at least one heteroatom selected from N, Oor S, or a 5- or 6-membered aromatic heterocyclic ring, which saturatedor aromatic heterocyclic ring is optionally substituted with C₁-C₃alkyland/or oxo;R^(Y4) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O, or S, which ring isoptionally substituted with C₁-C₃alkyl;R^(Y5) is independently selected from C₁-C₃alkyl, hydroxy,di(C₁-C₃alkyl)aminoC₁-C₃alkyl,ortwo R^(Y5) attached at the same carbon atom form together with thecarbon atom to which they are attached a 5-membered saturatedheterocyclic ring comprising at least one heteroatom selected from N, Oor S, which ring is substituted once or more than once with C₁-C₃alkyl;R^(Y6) and R^(Y7) together with the carbon atom to which they areattached form a 6-membered saturated or unsaturated non-aromaticheterocyclic ring comprising one heteroatom selected from N, O or S;R¹ is selected from hydrogen; halogen; C₁-C₃alkyl; haloC₁-C₃alkyl;hydroxyC₁-C₃alkyl; C₃-C₆cycloalkyl; CH₂NR²R³; CH(CH₃)NR²R³;C₁-C₃alkoxyC₁-C₃alkyl; CH₂CO₂H; C(O)H; C₁-C₃alkoxy; a 5- or 6-memberedsaturated heterocyclic or aromatic heterocyclic ring comprising at leastone heteroatom selected from N, O or S, which ring is optionallysubstituted once or more than once with a group independently selectedfrom C₁-C₃alkyl, haloC₁-C₃alkyl, oxetanyl or oxo;R² is selected from C₁-C₃alkyl, di(C₁-C₃alkyl)aminoC₁-C₃alkyl;R³ is selected from C₁-C₃alkyl, C(O)C₁-C₃alkyl, C(O)—CH₂—OH,C(O)—CH₂—O—CH₃, C(O)—CH₂—N(CH₃)₂, S(O)₂CH₃;orR² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, N-oxide, O or S, which ring may besubstituted once or more than once with R⁴;R⁴ is independently selected from C₁-C₃alkyl, di(C₁-C₃alkyl)amino,C(O)CH₃, hydroxy;ortwo R⁴ attached at the same carbon atom form together with the carbonatom to which they are attached a 4-, 5- or 6-membered non-aromaticheterocyclic ring comprising at least one heteroatom selected from N, Oor S;ortwo R⁴ attached at the same ring atom form an oxo group;R⁵ is selected from hydrogen or C₁-C₃alkylfor use in the treatment of solid malignancies characterized by positiveFGFR4 and KLB expression, or positive FGFR4 and FGF19 expression, orpositive FGFR4, KLB and FGF19 expression.

Unless specified otherwise, the terms “compounds of the presentinvention” or “compounds of the invention” or “compounds used in thepresent invention” refer to compounds of formula (I), (Ia), (Ia-1) andsalts thereof as defined herein, as well as all stereoisomers (includingdiastereoisomers and enantiomers), rotamers, tautomers, isomericinternal addition products and isotopically labeled compounds (includingdeuterium substitutions), as well as inherently formed moieties. Unlessotherwise defined, in the present description, a compound of formula (I)refers to:

whereinV is selected from CH₂, O, CH(OH);W is selected from CH₂, CH₂CH₂, bond;

X is C(R^(X)) or N; Y is C(R^(Y)) or N; Z is CH or N;

wherein when X is N, Y and Z are not N;wherein when Y is N, X and Z are not N;wherein when Z is N, X and Y are not N;R^(X) is selected from hydrogen, halogen, haloC₁-C₃alkyl, cyano,C₁-C₆alkyl, hydroxyC₁-C₆alkyl;R^(Y) is selected from hydrogen, halogen, C₁-C₃alkyl, C₁-C₆alkoxy,hydroxyC₁-C₃alkoxy, NR^(Y1)R^(Y2), cyano, C₁-C₃alkoxyC₁-C₃alkoxy,C₁-C₃alkoxy-haloC₁-C₃alkoxy, di(C₁-C₃alkyl)aminoC₁-C₆alkoxy,O—(CH₂)₀₋₁—R^(Y3), CR^(Y6)R^(Y7), S—C₁-C₃alkyl, haloC₁-C₆alkoxyoptionally substituted with hydroxy;orR^(X) and R^(Y) together with the ring to which they are attached form abicyclic aromatic ring system optionally further comprising one or twoheteroatoms selected from N, O, or S, which ring system is optionallysubstituted with C₁-C₃alkyl;R^(Y1) is hydrogen andR^(Y2) is selected from C₁-C₆alkyl; hydroxyC₁-C₆alkyl; haloC₁-C₆alkyloptionally substituted with hydroxy; C₁-C₄alkoxyC₁-C₆alkyl;haloC₁-C₃alkoxyC₁-C₆alkyl; (CH₂)₀₋₁—R^(Y4);di(C₁-C₃alkyl)aminoC₁-C₆alkyl substituted with hydroxy;bicycloC₅-C₈alkyl optionally substituted with hydroxyC₁-C₃alkyl; phenylsubstituted with S(O)₂—CH(CH₃)₂; C₂-C₃alkylsulfonic acid;orR^(Y1) and R^(Y2) together with the N atom to which they are attachedform a saturated or unsaturated non-aromatic 6-membered heterocyclicring which may contain an O atom, which ring may be substituted once ortwice by R^(Y5);R^(Y3) is selected from quinuclidinyl, a 4-, 5- or 6-membered saturatedheterocyclic ring comprising at least one heteroatom selected from N, Oor S, or a 5- or 6-membered aromatic heterocyclic ring, which saturatedor aromatic heterocyclic ring is optionally substituted with C₁-C₃alkyland/or oxo;R^(Y4) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O, or S, which ring isoptionally substituted with C₁-C₃alkyl;R^(Y5) is independently selected from C₁-C₃alkyl, hydroxy,di(C₁-C₃alkyl)aminoC₁-C₃alkyl,ortwo R^(Y5) attached at the same carbon atom form together with thecarbon atom to which they are attached a 5-membered saturatedheterocyclic ring comprising at least one heteroatom selected from N, Oor S, which ring is substituted once or more than once with C₁-C₃alkyl;R^(Y6) and R^(Y7) together with the carbon atom to which they areattached form a 6-membered saturated or unsaturated non-aromaticheterocyclic ring comprising one heteroatom selected from N, O or S;R¹ is selected from hydrogen; halogen; C₁-C₃alkyl; haloC₁-C₃alkyl;hydroxyC₁-C₃alkyl; C₃-C₆cycloalkyl; CH₂NR²R³; CH(CH₃)NR²R³;C₁-C₃alkoxyC₁-C₃alkyl; CH₂CO₂H; C(O)H; C₁-C₃alkoxy; a 5- or 6-memberedsaturated heterocyclic or aromatic heterocyclic ring comprising at leastone heteroatom selected from N, O or S, which ring is optionallysubstituted once or more than once with a group independently selectedfrom C₁-C₃alkyl, haloC₁-C₃alkyl, oxetanyl or oxo;R² is selected from C₁-C₃alkyl, di(C₁-C₃alkyl)aminoC₁-C₃alkyl;R³ is selected from C₁-C₃alkyl, C(O)C₁-C₃alkyl, C(O)—CH₂—OH,C(O)—CH₂—O—CH₃, C(O)—CH₂—N(CH₃)₂, S(O)₂CH₃;orR² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, N-oxide, O or S, which ring may besubstituted once or more than once with R⁴;R⁴ is independently selected from C₁-C₃alkyl, di(C₁-C₃alkyl)amino,C(O)CH₃, hydroxy;ortwo R⁴ attached at the same carbon atom form together with the carbonatom to which they are attached a 4-, 5- or 6-membered non-aromaticheterocyclic ring comprising at least one heteroatom selected from N, Oor S;ortwo R⁴ attached at the same ring atom form an oxo group;R⁵ is selected from hydrogen or C₁-C₃alkyl.

Unless otherwise defined, in the present description, a compound offormula (Ia) refers to:

whereinR^(X) is selected from hydrogen, halogen, haloC₁-C₃alkyl, cyano,C₁-C₆alkyl, hydroxyC₁-C₆alkyl;R^(Y) is selected from hydrogen, halogen, C₁-C₃alkyl, C₁-C₆alkoxy,hydroxyC₁-C₃alkoxy, NR^(Y1)R^(Y2), cyano, C₁-C₃alkoxyC₁-C₃alkoxy,C₁-C₃alkoxy-haloC₁-C₃alkoxy, di(C₁-C₃alkyl)aminoC₁-C₆alkoxy,O—(CH₂)₀₋₁—R^(Y3), CR^(Y6)R^(Y7), S—C₁-C₃alkyl, haloC₁-C₆alkoxyoptionally substituted with hydroxy;orR^(X) and R^(Y) together with the ring to which they are attached form abicyclic aromatic ring system optionally further comprising one or twoheteroatoms selected from N, O, or S, which ring system is optionallysubstituted with C₁-C₃alkyl;R¹ is hydrogen andR^(Y2) is selected from C₁-C₆alkyl; hydroxyC₁-C₆alkyl; haloC₁-C₆alkyloptionally substituted with hydroxyl; C₁-C₄alkoxyC₁-C₆alkyl;haloC₁-C₃alkoxyC₁-C₆alkyl; (CH₂)₀₋₁—R^(Y4);di(C₁-C₃alkyl)aminoC₁-C₆alkyl substituted with hydroxy;bicycloC₅-C₈alkyl optionally substituted with hydroxyC₁-C₃alkyl; phenylsubstituted with S(O)₂—CH(CH₃)₂; C₂-C₃alkylsulfonic acid;orR^(Y1) and R^(Y2) together with the N atom to which they are attachedform a saturated or unsaturated non-aromatic 6-membered heterocyclicring which may contain an O atom, which ring may be substituted once ortwice by R^(Y5);R^(Y3) is selected from quinuclidinyl, a 4-, 5- or 6-membered saturatedheterocyclic ring comprising at least one heteroatom selected from N, Oor S, or a 5- or 6-membered aromatic heterocyclic ring, which saturatedor aromatic heterocyclic ring is optionally substituted with C₁-C₃alkyland/or oxo;R^(Y4) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O, or S, which ring isoptionally substituted with C₁-C₃alkyl;R^(Y5) is independently selected from C₁-C₃alkyl, hydroxy,di(C₁-C₃alkyl)aminoC₁-C₃alkyl,ortwo R^(Y5) attached at the same carbon atom form together with thecarbon atom to which they are attached a 5-membered saturatedheterocyclic ring comprising at least one heteroatom selected from N, Oor S, which ring is substituted with C₁-C₃alkyl;R^(Y6) and R^(Y7) together with the carbon atom to which they areattached form a 6-membered saturated or unsaturated non-aromaticheterocyclic ring comprising one heteroatom selected from N, O or S;R¹ is selected from hydrogen, halogen, C₁-C₃alkyl, haloC₁-C₃alkyl,hydroxyC₁-C₃alkyl, C₃-C₆cycloalkyl, CH₂NR²R³, CH(CH₃)NR²R³,C₁-C₃alkoxyC₁-C₃alkyl, CH₂CO₂H, C(O)H;R² is selected from C₁-C₃alkyl, di(C₁-C₃alkyl)aminoC₁-C₃alkyl;R³ is selected from C₁-C₃alkyl, C(O)C₁-C₃alkyl, C(O)—CH₂—OH,C(O)—CH₂—O—CH₃, C(O)—CH₂—N(CH₃)₂, S(O)₂CH₃;orR² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, N-oxide, O or S, which ring may besubstituted once or more than once with R⁴;R⁴ is independently selected from C₁-C₃alkyl, di(C₁-C₃alkyl)amino,C(O)CH₃, hydroxy;ortwo R⁴ attached at the same carbon atom form together with the carbonatom to which they are attached a 4-, 5- or 6-membered non-aromaticheterocyclic ring comprising at least one heteroatom selected from N, Oor S;ortwo R⁴ attached at the same ring atom form an oxo group.

Unless otherwise defined, in the present description, a compound offormula (Ia-1) refers to:

whereinR^(Y) is selected from hydrogen, halogen, C₁-C₃alkyl, C₁-C₆alkoxy,hydroxyC₁-C₃alkoxy, NR^(Y)R^(Y2), cyano, C₁-C₃alkoxyC₁-C₃alkoxy,C₁-C₃alkoxy-haloC₁-C₃alkoxy, di(C₁-C₃alkyl)aminoC₁-C₆alkoxy,O—(CH₂)₀₋₁—R^(Y3), CR^(Y6)R^(Y7), S—C₁-C₃alkyl, haloC₁-C₆alkoxyoptionally substituted with hydroxy;R^(Y1) is hydrogen andR^(Y2) is selected from C₁-C₆alkyl; hydroxyC₁-C₆alkyl; haloC₁-C₆alkyloptionally substituted with hydroxyl; C₁-C₄alkoxyC₁-C₆alkyl;haloC₁-C₃alkoxyC₁-C₆alkyl; (CH₂)₀₋₁—R^(Y4);di(C₁-C₃alkyl)aminoC₁-C₆alkyl substituted with hydroxy;bicycloC₅-C₈alkyl optionally substituted with hydroxyC₁-C₃alkyl; phenylsubstituted with S(O)₂—CH(CH₃)₂; C₂-C₃alkylsulfonic acid;orR^(Y1) and R^(Y2) together with the N atom to which they are attachedform a saturated or unsaturated non-aromatic 6-membered heterocyclicring which may contain an O atom, which ring may be substituted once ortwice by R^(Y5);R^(Y3) is selected from quinuclidinyl, a 4-, 5- or 6-membered saturatedheterocyclic ring comprising at least one heteroatom selected from N, Oor S, or a 5- or 6-membered aromatic heterocyclic ring, which saturatedor aromatic heterocyclic ring is optionally substituted with C₁-C₃alkyland/or oxo;R^(Y4) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O, or S, which ring isoptionally substituted with C₁-C₃alkyl;R^(Y5) is independently selected from C₁-C₃alkyl, hydroxy,di(C₁-C₃alkyl)aminoC₁-C₃alkyl,ortwo R^(Y5) attached at the same carbon atom form together with thecarbon atom to which they are attached a 5-membered saturatedheterocyclic ring comprising at least one heteroatom selected from N, Oor S, which ring is substituted with C₁-C₃alkyl;R^(Y6) and R^(Y7) together with the carbon atom to which they areattached form a 6-membered saturated or unsaturated non-aromaticheterocyclic ring comprising one heteroatom selected from N, O or S;R¹ is selected from hydrogen, halogen, C₁-C₃alkyl, haloC₁-C₃alkyl,hydroxyC₁-C₃alkyl, C₃-C₆cycloalkyl, CH₂NR²R³, CH(CH₃)NR²R³,C₁-C₃alkoxyC₁-C₃alkyl, CH₂CO₂H, C(O)H;R² is selected from C₁-C₃alkyl, di(C₁-C₃alkyl)aminoC₁-C₃alkyl;R³ is selected from C₁-C₃alkyl, C(O)C₁-C₃alkyl, C(O)—CH₂—OH,C(O)—CH₂—O—CH₃, C(O)—CH₂—N(CH₃)₂, S(O)₂CH₃;orR² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, N-oxide, O or S, which ring may besubstituted once or more than once with R⁴;R⁴ is independently selected from C₁-C₃alkyl, di(C₁-C₃alkyl)amino,C(O)CH₃, hydroxy;ortwo R⁴ attached at the same carbon atom form together with the carbonatom to which they are attached a 4-, 5- or 6-membered non-aromaticheterocyclic ring comprising at least one heteroatom selected from N, Oor S;ortwo R⁴ attached at the same ring atom form an oxo group.

In particular, the compounds of formula (I), (Ia), (Ia-1) are able toreadily form tautomers and isomeric internal addition products asdepicted below.

For instance, compounds of the invention where R¹ is hydroxymethyl,CH₂CO₂H, 4-piperidinyl e.g. compounds (I-1), (I-2) and (I-5), may be inthe form as depicted below (compounds (I-1a), (I-2a) and (1-5a)).

Thus, the compounds (I-1), (I-2), (I-5) and their isomers (I-1a),(I-2a), (I-5a) wherein V, W, X, Y and Z are as defined herein, also formpart of the invention.

The presence of tautomers or isomeric internal additional products canbe identified by a person of skill in the art with tools such as NMR.

As used herein, the term “C₁-C₆alkyl” refers to a straight or branchedhydrocarbon chain radical consisting solely of carbon and hydrogenatoms, containing no unsaturation, having from one to six carbon atoms,and which is attached to the rest of the molecule by a single bond. Theterm “C₁-C₄alkyl” is to be construed accordingly. The term “C₁-C₃alkyl”is to be construed accordingly. Examples of C₁-C₆alkyl include, but arenot limited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),n-butyl, n-pentyl and 1,1-dimethylethyl (t-butyl).

As used herein, the term “hydroxyC₁-C₆alkyl” refers to a radical offormula —R_(a)—OH, wherein R_(a) is C₁₋₆alkyl as defined above. Examplesof hydroxyC₁-C₆alkyl include, but are not limited to, hydroxy-methyl,2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl and5-hydroxy-pentyl.

As used herein, the term “C₃-C₆cycloalkyl” refers to saturatedmonocyclic hydrocarbon groups of 3-6 carbon atoms. Examples ofC₃-C₆cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

As used herein, the term “C₁-C₆alkoxy” refers to a radical of theformula —OR_(a) where R_(a) is a C₁-C₆alkyl radical as generally definedabove. The term “C₁-C₃alkoxy” is to be construed accordingly.

Examples of C₁-C₆alkoxy include, but are not limited to, methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.

As used herein, the term “C₁-C₄alkoxyC₁-C₆alkyl” refers to a radical ofthe formula —R_(b)—O—R_(a) where R_(a) is a C₁-C₄alkyl radical and R_(b)is a C₁-C₆alkyl radical as defined above. The term“C₁-C₃alkoxyC₁-C₆alkyl” is to be construed accordingly. The oxygen atommay be bonded to any carbon atom in either alkyl radical. Examples ofC₁-C₄alkoxyC₁-C₆alkyl include, but are not limited to, methoxy-methyl,methoxy-ethyl, ethoxy-ethyl, 1-ethoxy-propyl and 2-methoxy-butyl.

“Halogen” or “halo” refers to bromo, chloro, fluoro or iodo.

As used herein, the term “halogenC₁-C₆alkyl” or “haloC₁-C₆alkyl” refersto C₁-C₆alkyl radical, as defined above, substituted by one or more haloradicals, as defined above. Examples of halogenC₁-C₆alkyl include, butare not limited to, trifluoromethyl, difluoromethyl, fluoromethyl,trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl,3-bromo-2-fluoropropyl and 1-bromomethyl-2-bromoethyl.

As used herein, the term “haloC₁-C₃alkoxy” refers to C₁-C₃alkoxy asdefined above, substituted by one or more halo radicals, as definedabove. Examples of haloC₁-C₃alkoxy include, but are not limited to,trifluoromethoxy, difluoromethoxy, trifluoroethoxy.

As used herein, the term “hydroxyC₁-C₃alkoxy” refers to a C₁-C₃alkoxyradical as defined above, wherein one of the hydrogen atoms of theC₁-C₃alkoxy radical is replaced by OH. Examples of hydroxyC₁-C₃alkoxyinclude, but are not limited to, hydroxymethoxy, hydroxyethoxy.

As used herein, the term “C₁-C₃alkoxyC₁-C₃alkoxy” refers to aC₁-C₃alkoxy radical as defined above, wherein one of the hydrogen atomsof the C₁₋₃alkoxy radical is replaced by —O—C₁-C₃alkyl. Examples ofC₁-C₃alkoxyC₁-C₃alkoxy include, but are not limited to, methoxymethoxy,ethoxymethoxy.

As used herein, the term “C₁-C₃alkoxy-haloC₁-C₃alkoxy” refers to ahaloC₁-C₃alkoxy radical as defined above, wherein one of the hydrogenatoms of the haloC₁-C₃alkoxy radical is replaced by —O—C₁-C₃alkyl.Examples of C₁-C₃alkoxy-haloC₁-C₃alkoxy include, but are not limited to,methoxytrifluoropropyloxy.

As used herein, the term “di(C₁-C₃alkyl)aminoC₁-C₆alkyl” refers to aradical of the formula —R_(a1)—N(R_(a2))—R_(a2) where R_(a1) is aC₁-C₆alkyl radical as defined above and each R_(a2) is a C₁-C₃alkylradical, which may be the same or different, as defined above. Thenitrogen atom may be bonded to any carbon atom in any alkyl radical. Asdescribed herein, the “diC₁-C₃alkylaminoC₁-C₆alkyl” may be substitutedwith hydroxy.

As used herein, the term “di(C₁-C₃alkyl)aminoC₁-C₆alkoxy” refers to aradical of the formula —R_(a1)—N(R_(a2))—R_(a2) where R_(a1) is aC₁-C₆alkoxy radical as defined above and each R_(a2) is a C₁-C₃alkylradical, which may be the same or different, as defined above.

As used herein, the term “6-membered saturated heterocyclic ringcomprising one heteroatom selected from N, O or S” includes piperidyl,tetrahydropyranyl and tetrahydrothiopyranyl.

As used herein, the term “6-membered unsaturated non-aromaticheterocyclic ring comprising one heteroatom selected from N, O or S”includes, but is not limited to, tetrahydropyridinyl, dihydropyranyl,dihydrothiopyranyl.

As used herein, the term “a 4-, 5-, or 6-membered saturated heterocyclicring comprising at least one heteroatom selected from N, O or S”includes as examples, but is not limited to, azetidinyl, oxetanyl,pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl,tetrahydropyranyl, morpholinyl.

As used herein, the term “5-membered saturated heterocyclic ring”includes as example, but is not limited to, pyrrolidine.

As used herein, the term “a saturated 5- or 6-membered ring optionallycomprising one additional heteroatom selected from N, O or S” inrelation to the embodiments where R² and R³ together with the N atom towhich they are attached form said ring, includes as examples, but is notlimited to, pyrrolidine, oxazolidine, piperazine, morpholine,thiomorpholine rings.

As used herein, the term a “4-, 5- or 6-membered non-aromaticheterocyclic ring comprising at least one heteroatom selected from N, Oor S” includes 4-, 5-, or 6-membered saturated heterocyclic ringcomprising at least one heteroatom selected from N, O or S as definedherein. It also includes 4-, 5-, or 6-membered unsaturated heterocyclicring comprising at least one heteroatom selected from N, O or S.

As used herein, the term “bicyclic aromatic ring system optionallyfurther comprising one or two heteroatoms selected from N, O or S”includes, but is not limited to, imidazopyridine andisothiazolopyridine.

As used herein, the term “bicycloC₅-C₈alkyl” refers to bicyclichydrocarbon groups comprising 5 to 8 carbon atoms including, but notlimited to, bicyclo[2.1.1]hexyl, bicyclo[1.1.1]pentyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octyl.

As used herein, the term “optionally substituted” as used in thedescription of R^(Y), R^(X) and R^(Y) together, R^(Y2), R^(Y3), R^(Y4)includes unsubstituted or substituted once or twice.

As used herein, the term “substituted” as used, for example in thedescription of R^(Y2), two R^(Y5), includes substituted once or twice,preferably once.

As used herein, the term “more than once” when referring to substituentR⁴, includes 2, 3, 4, 5, or 6 times. Preferably, it includes 2 or 3times.

As used herein, the term “solid malignancies” refers tonon-hematological malignancies.

As used herein, the term “FGFR4” refers to fibroblast growth factorreceptor 4, also known as CD334, JTK2, TKF (gene ID: 2264).

As used herein, the term “FGF19” refers to fibroblast growth factor 19(gene ID: 9965) As used herein, the term “KLB” refers to the beta-klothoprotein (gene ID: 152831).

As used herein, the term “biomarkers of the invention” refers to any ofFGFR4, KLB and FGF19. Any positive expression in FGFR4, KLB and/or FGF19as described herein can be assessed by methods known to the skilledperson such as e.g. RT-qPCR, Western blotting, ELISA,immunohistochemistry. For example, any positive expression in FGFR4, KLBand/or FGF19 can be assayed by detecting for expression of the RNAlevels of FGFR4, KLB and/or FGF19 or detecting expression of the FGFR4,KLB and/or FGF19 protein product by methods known to the skilled person.It is within the reach of the skilled person to determine a positiveexpression of FGFR4, FGF19 and/or KLB.

For example, the positive expression in FGFR4, KLB and/or FGF19 can beassessed as described in the examples.

The term “assaying” is used to refer to the act of identifying,screening, probing or determining, which act may be performed by anyconventional means. For example, a sample may be assayed for thepresence of a particular biomarker by using an ELISA assay, a Northernblot, imaging, etc. to detect whether a specific biomarker is present inthe sample. The terms “assaying” and “determining” contemplate atransformation of matter, e.g., a transformation of a biological sample,e.g., a blood sample or other tissue sample, from one state to anotherby means of subjecting that sample to physical testing. Further, as usedherein, the terms “assaying” and “determining” are used to mean testingand/or measuring. The phrase “assaying a biological sample from thepatient for the presence or the positive expression of FGF19 or FGF19and KLB or FGFR4, FGF19 and/or KLB” and the like is used to mean that asample may be tested (either directly or indirectly) for either thepresence or absence of a given biomarker or for the level of aparticular biomarker. It will be understood that the positive expressionof a biomarker FGFR4, KLB and/or FGF19 in a substance denotes oneprobability and the absence of a substance denotes a differentprobability, then either the presence or the absence of such substancemay be used to guide a therapeutic decision.

As used herein, “selecting” and “selected” in reference to a patient isused to mean that a particular patient is specifically chosen from alarger group of patients on the basis of (due to) the particular patienthaving a predetermined criteria. Similarly, “selectively treating”refers to providing treatment to a patient having a particular disease,where that patient is specifically chosen from a larger group ofpatients on the basis of the particular patient having a predeterminedcriterion. Similarly, “selectively administering” refers toadministering a drug to a patient that is specifically chosen from alarger group of patients on the basis of (due to) the particular patienthaving a predetermined criterion. By selecting, selectively treating andselectively administering, it is meant that a patient is delivered apersonalized therapy based on the patient's particular biology, ratherthan being delivered a standard treatment regimen based solely on thepatient having a particular disease. Selecting, in reference to a methodof treatment as used herein, does not refer to fortuitous treatment of apatient that has the biomarker, but rather refers to the deliberatechoice to administer treatment to a patient based on the patient havingpositive expression of the biomarker. Thus, selective treatment differsfrom standard treatment, which delivers a particular drug to allpatients, regardless of their biomarker.

As used herein, “likelihood” and “likely” is a measurement of howprobable an event is to occur. It may be used interchangeably with“probability”. Likelihood refers to a probability that is more thanspeculation, but less than certainty. Thus, an event is likely if areasonable person using common sense, training or experience concludesthat, given the circumstances, an event is probable. In someembodiments, once likelihood has been ascertained, the patient may betreated (or treatment continued, or treatment proceed with a dosageincrease) with the test compound. In one embodiment, the “likelihood”and “likely” denote a chance in percent of how probable an event is tooccur.

The phrase “increased likelihood” refers to an increase in theprobability that an event will occur. For example, some methods hereinallow prediction of whether a patient will display an increasedlikelihood of responding to treatment with the test molecule or anincreased likelihood of responding better to treatment with the testmolecule. In one embodiment the increased likelihood means that there ismore than 50% chance, more than 60% chance, more than 70% or more than80% chance that an event will occur. Equally, a decreased likelihoodmeans, that the chance is lower than 50%, lower than 60%, lower than 70%or lover than 80%, respectively, that an event will occur.

In an embodiment of the invention, there is provided a compound offormula (Ia) or a pharmaceutically acceptable salt thereof for use inthe treatment of solid malignancies characterized by positive FGFR4 andKLB expression, or positive FGFR4 and FGF19 expression, or positiveFGFR4, KLB and FGF19 expression.

In an embodiment of the invention, there is provided a compound offormula (Ia) or a pharmaceutically acceptable salt thereof

whereinR^(X) is selected from halogen, haloC₁-C₃alkyl, cyano;R^(Y) is selected from hydrogen, halogen, C₁-C₃alkyl, C₁-C₆alkoxy,haloC₁-C₃alkoxy, hydroxyC₁-C₃alkoxy, NR^(Y1)R^(Y2),C₁-C₃alkoxyC₁-C₃alkoxy, C₁-C₃alkoxy-haloC₁-C₃alkoxy, O—(CH₂)₀₋₁—R^(Y3);R^(Y1) is hydrogen and R^(Y2) is selected from C₁-C₆alkyl,hydroxyC₁-C₆alkyl, C₁-C₃alkoxyC₁-C₆alkyl, (CH₂)₀₋₁—R^(Y4),haloC₁-C₆alkyl optionally substituted with hydroxyl;R^(Y3) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O or S, which ring isoptionally substituted with C₁-C₃alkyl;R^(Y4) is a 4-, 5-, or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O or S, which ring isoptionally substituted with C₁-C₃alkyl;R¹ is selected from hydrogen, halogen, C₁-C₃alkyl, haloC₁-C₃alkyl,hydroxyC₁-C₃alkyl, C₃-C₆cycloalkyl, CH₂NR²R³, CH(CH₃)NR²R³;R² is C₁-C₃alkyl and R³ is selected from C₁-C₃alkyl, C(O)—C₁-C₃alkyl orR² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, O or S, which ring may be substituted onceor more than once with R⁴;R⁴ is independently selected from C₁-C₃alkyl, di(C₁-C₃alkyl)amino or twoR₄ attached at the same carbon atom form an oxo groupfor use in the treatment of solid malignancies characterized by positiveFGFR4 expression or positive FGFR4 and KLB expression, or positive FGFR4and FGF19 expression, or positive FGFR4, KLB and FGF19 expression.

In an embodiment of the invention, there is provided a compound offormula (Ia-1) or a pharmaceutically acceptable salt thereof for use inthe treatment of solid malignancies characterized by positive FGFR4 andKLB expression, or positive FGFR4 and FGF19 expression, or positiveFGFR4, KLB and FGF19 expression.

In an embodiment of the invention, there is provided a compound offormula (Ia-1) or a pharmaceutically acceptable salt thereof

whereinR^(Y) is selected from hydrogen, halogen, C₁-C₃alkyl, C₁-C₆alkoxy,haloC₁-C₃alkoxy, hydroxyC₁-C₃alkoxy, NR^(Y1)R^(Y2),C₁-C₃alkoxyC₁-C₃alkoxy, C₁-C₃alkoxy-haloC₁-C₃alkoxy, O—(CH₂)₀₋₁—R^(Y3);R^(Y1) is hydrogen and R^(Y2) is C₁-C₆alkyl, hydroxyC₁-C₆alkyl,C₁-C₄alkoxyC₁-C₆alkyl, (CH₂)₀₋₁—R^(Y4), haloC₁-C₆alkyl optionallysubstituted with hydroxyl;R^(Y3) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O or S, which ring isoptionally substituted with C₁-C₃alkyl;R^(Y4) is a 4-, 5-, or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O or S, which ring isoptionally substituted with C₁-C₃alkyl;R¹ is selected from hydrogen, halogen, C₁-C₃alkyl, haloC₁-C₃alkyl,hydroxyC₁-C₃alkyl, C₃-C₆cycloalkyl, CH₂NR²R³, CH(CH₃)NR²R³;R² is C₁-C₃alkyl and R³ is selected from C₁-C₃alkyl, C(O)—C₁-C₃alkyl orR² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, O or S, which ring may be substituted onceor more than once with R⁴;R⁴ is independently selected from C₁-C₃alkyl, di(C₁-C₃alkyl)amino or twoR₄ attached at the same carbon atom form an oxo groupfor use in the treatment of solid malignancies characterized by positiveFGFR4 and KLB expression, or positive FGFR4 and FGF19 expression, orpositive FGFR4, KLB and FGF19 expression.

In an embodiment of the invention, there is provided a compound offormula (Ia-1) or a pharmaceutically acceptable salt thereof

wherein R^(Y) is selected from NR^(Y1)R^(Y2), C₁-C₃alkoxyC₁-C₃alkoxy,O—(CH₂)₀₋₁—R^(Y3);R^(Y1) is hydrogen andR^(Y2) is selected from C₁-C₆alkyl; hydroxyC₁-C₆alkyl; haloC₁-C₆alkyloptionally substituted with hydroxyl; C₁-C₄alkoxyC₁-C₆alkyl;haloC₁-C₃alkoxyC₁-C₆alkyl; (CH₂)₀₋₁—R^(Y4);di(C₁-C₃alkyl)aminoC₁-C₆alkyl substituted with hydroxy;bicycloC₅-C₈alkyl optionally substituted with hydroxyC₁-C₃alkyl; phenylsubstituted with S(O)₂—CH(CH₃)₂; C₂-C₃alkylsulfonic acid;orR^(Y1) and R^(Y2) together with the N atom to which they are attachedform a saturated or unsaturated non-aromatic 6-membered heterocyclicring which may contain an O atom, which ring may be substituted once ortwice by R^(Y5);R^(Y3) is selected from quinuclidinyl, a 4-, 5- or 6-membered saturatedheterocyclic ring comprising at least one heteroatom selected from N, Oor S, or a 5- or 6-membered aromatic heterocyclic ring, which saturatedor aromatic heterocyclic ring is optionally substituted with C₁-C₃alkyland/or oxo;R^(Y4) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O, or S, which ring isoptionally substituted with C₁-C₃alkyl;R^(Y5) is independently selected from C₁-C₃alkyl, hydroxy,di(C₁-C₃alkyl)aminoC₁-C₃alkyl,ortwo R^(Y5) attached at the same carbon atom form together with thecarbon atom to which they are attached a 5-membered saturatedheterocyclic ring comprising at least one heteroatom selected from N, Oor S, which ring is substituted with C₁-C₃alkyl;R^(Y6) and R^(Y7) together with the carbon atom to which they areattached form a 6-membered saturated or unsaturated non-aromaticheterocyclic ring comprising one heteroatom selected from N, O or S;R¹ is selected from hydrogen, halogen, C₁-C₃alkyl, haloC₁-C₃alkyl,hydroxyC₁-C₃alkyl, C₃-C₆cycloalkyl, CH₂NR²R³, CH(CH₃)NR²R³,C₁-C₃alkoxyC₁-C₃alkyl, CH₂CO₂H, C(O)H;R² is selected from C₁-C₃alkyl, di(C₁-C₃alkyl)aminoC₁-C₃alkyl;R³ is selected from C₁-C₃alkyl, C(O)C₁-C₃alkyl, C(O)—CH₂—OH,C(O)—CH₂—O—CH₃, C(O)—CH₂—N(CH₃)₂, S(O)₂CH₃;orR² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, N-oxide, O or S, which ring may besubstituted once or more than once with R⁴;R⁴ is independently selected from C₁-C₃alkyl, di(C₁-C₃alkyl)amino,C(O)CH₃, hydroxy;ortwo R⁴ attached at the same carbon atom form together with the carbonatom to which they are attached a 4-, 5- or 6-membered non-aromaticheterocyclic ring comprising at least one heteroatom selected from N, Oor S;ortwo R⁴ attached at the same ring atom form an oxo groupfor use in the treatment of solid malignancies characterized by positiveFGFR4 and KLB expression, or positive FGFR4 and FGF19 expression, orpositive FGFR4, KLB and FGF19 expression.

In an embodiment of the invention, there is provided a compound offormula (Ia-1) or a pharmaceutically acceptable salt thereof

whereinR^(Y) is selected from NR^(Y1)R^(Y2), C₁-C₃alkoxyC₁-C₃alkoxy,O—(CH₂)₀₋₁—R^(Y3);R^(Y3) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O or S, which ring isoptionally substituted with C₁-C₃alkyl;R^(Y1) is hydrogen and R^(Y2) is C₁-C₆alkyl, C₁-C₃alkoxyC₁-C₆alkyl,(CH₂)₀₋₁—R^(Y4);R^(Y4) is a 4-, 5-, or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O or S, which ring isoptionally substituted with C₁-C₃alkyl;R¹ is selected from hydrogen, halogen, C₁-C₃alkyl, haloC₁-C₃alkyl,hydroxyC₁-C₃alkyl, C₃-C₆cycloalkyl, CH₂NR²R³, CH(CH₃)NR²R³;R² is C₁-C₃alkyl and R³ is selected from C₁-C₃alkyl, C(O)—C₁-C₃alkyl orR² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, O or S, which ring may be substituted onceor more than once with R⁴;R⁴ is independently selected from C₁-C₃alkyl, di(C₁-C₃alkyl)amino or twoR₄ attached at the same carbon atom form an oxo groupfor use in the treatment of solid malignancies characterized by positiveFGFR4 and KLB expression, or positive FGFR4 and FGF19 expression, orpositive FGFR4, KLB and FGF19 expression.

In an embodiment of the invention, there is provided a compound offormula (Ia-1) or a pharmaceutically acceptable salt thereof

wherein R^(Y) is selected from NR^(Y1)R^(Y2), C₁-C₃alkoxyC₁-C₃alkoxy;R¹ is hydrogen andR^(Y2) is selected from C₁-C₆alkyl; hydroxyC₁-C₆alkyl; haloC₁-C₆alkyloptionally substituted with hydroxyl; C₁-C₄alkoxyC₁-C₆alkyl;haloC₁-C₃alkoxyC₁-C₆alkyl; (CH₂)₀₋₁—R^(Y4);di(C₁-C₃alkyl)aminoC₁-C₆alkyl substituted with hydroxy;bicycloC₅-C₈alkyl optionally substituted with hydroxyC₁-C₃alkyl; phenylsubstituted with S(O)₂—CH(CH₃)₂; C₂-C₃alkylsulfonic acid;orR^(Y1) and R^(Y2) together with the N atom to which they are attachedform a saturated or unsaturated non-aromatic 6-membered heterocyclicring which may contain an O atom, which ring may be substituted once ortwice by R^(Y5);R^(Y4) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O, or S, which ring isoptionally substituted with C₁-C₃alkyl;R^(Y5) is independently selected from C₁-C₃alkyl, hydroxy,di(C₁-C₃alkyl)aminoC₁-C₃alkyl,ortwo R^(Y5) attached at the same carbon atom form together with thecarbon atom to which they are attached a 5-membered saturatedheterocyclic ring comprising at least one heteroatom selected from N, Oor S, which ring is substituted with C₁-C₃alkyl;R¹ is selected from hydrogen, halogen, C₁-C₃alkyl, haloC₁-C₃alkyl,hydroxyC₁-C₃alkyl, C₃-C₆cycloalkyl, CH₂NR²R³, CH(CH₃)NR²R³,C₁-C₃alkoxyC₁-C₃alkyl, CH₂CO₂H, C(O)H;R² is selected from C₁-C₃alkyl, di(C₁-C₃alkyl)aminoC₁-C₃alkyl;R³ is selected from C₁-C₃alkyl, C(O)C₁-C₃alkyl, C(O)—CH₂—OH,C(O)—CH₂—O—CH₃, C(O)—CH₂—N(CH₃)₂, S(O)₂CH₃;orR² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, N-oxide, O or S, which ring may besubstituted once or more than once with R⁴;R⁴ is independently selected from C₁-C₃alkyl, di(C₁-C₃alkyl)amino,C(O)CH₃, hydroxy;ortwo R⁴ attached at the same carbon atom form together with the carbonatom to which they are attached a 4-, 5- or 6-membered non-aromaticheterocyclic ring comprising at least one heteroatom selected from N, Oor S;ortwo R⁴ attached at the same ring atom form an oxo groupfor use in the treatment of solid malignancies characterized by positiveFGFR4 and KLB expression, or positive FGFR4 and FGF19 expression, orpositive FGFR4, KLB and FGF19 expression.

In an embodiment of the invention, there is provided a compound offormula (Ia-1) or a pharmaceutically acceptable salt thereof

whereinR^(Y) is selected from NR^(Y1)R^(Y2), C₁-C₃alkoxyC₁-C₃alkoxy;R^(Y1) is hydrogen and R^(Y2) is selected from C₁-C₆alkyl,C₁-C₃alkoxyC₁-C₆alkyl, (CH₂)₀₋₁—R^(Y4);R^(Y4) is a 4-, 5-, or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O or S, which ring isoptionally substituted with C₁-C₃alkyl;R¹ is selected from CH₂NR²R³, CH(CH₃)NR²R³;R² is C₁-C₃alkyl and R³ is selected from C₁-C₃alkyl, C(O)—C₁-C₃alkyl orR² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, O or S, which ring may be substituted onceor more than once with R⁴;R⁴ is independently selected from C₁-C₃alkyl, di(C₁-C₃alkyl)amino or twoR₄ attached at the same carbon atom form an oxo groupfor use in the treatment of solid malignancies characterized by positiveFGFR4 and KLB expression, or positive FGFR4 and FGF19 expression, orpositive FGFR4, KLB and FGF19 expression.

In an embodiment, the compound of formula (I), (Ia) or (Ia-1) used inthe present invention is selected from

-   N-(5-cyanopyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;-   N-(5-cyanopyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;-   N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;-   (R)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;-   (S)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;-   N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-(difluoromethyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;-   N-(5-cyanopyridin-2-yl)-7-formyl-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;-   N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;-   N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;-   N-(5-cyano-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;-   N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;-   (R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide    or pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and KLBexpression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4, KLB and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and KLB expression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4, KLB and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and KLBexpression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4, KLB and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and KLB expression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4, KLB and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and KLBexpression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4, KLB and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and KLB expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4, KLB and FGF19 expression.

In another embodiment of the present invention, there is provided(R)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and KLBexpression.

In another embodiment of the present invention, there is provided(R)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and FGF19expression.

In another embodiment of the present invention, there is provided(R)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4, KLB and FGF19expression.

In another embodiment of the present invention, there is provided(R)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and KLB expression.

In another embodiment of the present invention, there is provided(R)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and FGF19 expression.

In another embodiment of the present invention, there is provided(R)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4, KLB and FGF19 expression.

In another embodiment of the present invention, there is provided(S)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and KLBexpression.

In another embodiment of the present invention, there is provided(S)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and FGF19expression.

In another embodiment of the present invention, there is provided(S)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4, KLB and FGF19expression.

In another embodiment of the present invention, there is provided(S)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and KLB expression.

In another embodiment of the present invention, there is provided(S)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and FGF19 expression.

In another embodiment of the present invention, there is provided(S)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4, KLB and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-(difluoromethyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and KLBexpression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-(difluoromethyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-(difluoromethyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4, KLB and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-(difluoromethyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and KLB expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-(difluoromethyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-(difluoromethyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4, KLB and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and KLBexpression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4, KLB and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and KLB expression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyanopyridin-2-yl)-7-formyl-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4, KLB and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and KLBexpression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4, KLB and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and KLB expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4, KLB and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and KLBexpression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4, KLB and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and KLB expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4, KLB and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and KLBexpression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4, KLB and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and KLB expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4, KLB and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and KLBexpression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4, KLB and FGF19expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and KLB expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and FGF19 expression.

In another embodiment of the present invention, there is providedN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4, KLB and FGF19 expression.

In another embodiment of the present invention, there is provided(R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and KLBexpression.

In another embodiment of the present invention, there is provided(R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4 and FGF19expression.

In another embodiment of the present invention, there is provided(R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof solid malignancies characterized by positive FGFR4, KLB and FGF19expression.

In another embodiment of the present invention, there is provided(R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and KLB expression.

In another embodiment of the present invention, there is provided(R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4 and FGF19 expression.

In another embodiment of the present invention, there is provided(R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideor a pharmaceutically acceptable salt thereof for use in the treatmentof liver cancer, breast cancer, glioblastoma, prostate cancer,rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or coloncancer characterized by positive FGFR4, KLB and FGF19 expression.

In an embodiment of the invention, there is provided a compound offormula (I), (Ia) or (Ia-1) or a pharmaceutically acceptable saltthereof for use in treating a patient having solid malignancies,characterized in that the compound of formula (I) or a pharmaceuticallyacceptable salt thereof is to be administered to the patient on thebasis of said patient having positive FGFR4 and KLB expression, orpositive FGFR4 and FGF19 expression, or positive FGFR4, KLB and FGF19expression.

In an embodiment of the invention, there is provided a compound offormula (I), (Ia) or (Ia-1) or a pharmaceutically acceptable saltthereof for use in treating a patient having solid malignancies,characterized in that

-   -   a. The patient is selected for treatment with a compound of        formula (I), (Ia) or (Ia-1) or a pharmaceutically acceptable        salt thereof on the basis of the patient having positive FGFR4        and KLB expression, or positive FGFR4 and FGF19 expression, or        positive FGFR4, KLB and FGF19 expression; and    -   b. Thereafter, a compound of formula (I), (Ia) or (Ia-1) or a        pharmaceutically acceptable salt thereof is administered to the        patient.

In an embodiment of the invention, there is provided a compound offormula (I), (Ia) or (Ia-1) or a pharmaceutically acceptable saltthereof for use in treating a patient having solid malignancies,characterized in that

-   -   a. A biological sample from a patient is assayed for positive        FGFR4 and KLB expression, or positive FGFR4 and FGF19        expression, or positive FGFR4, KLB and FGF19 expression; and    -   b. a compound of formula (I), (Ia) or (Ia-1) or a        pharmaceutically acceptable salt thereof is administered to the        patient on the basis of the biological sample from the patient        having positive FGFR4 and KLB expression, or positive FGFR4 and        FGF19 expression, or positive FGFR4, KLB and FGF19 expression.

In an embodiment of the invention, there is provided a compound offormula (I), (Ia) or (Ia-1) or a pharmaceutically acceptable saltthereof for use in treating a patient having solid malignanciescomprising

-   -   a. Assaying a biological sample from the patient    -   b. Determining if the biological sample from the patient is        characterized by positive FGFR4 and KLB expression, or by        positive FGFR4 and FGF19 expression, or by positive FGFR4, KLB        and FGF19 expression, and    -   c. If the biological sample is characterized by positive FGFR4        and KLB expression, or by positive FGFR4 and FGF19 expression,        or by positive FGFR4, KLB and FGF19 expression, administering a        compound of formula (I), (Ia) or (Ia-1) or a pharmaceutically        acceptable salt thereof to the patient.

In an embodiment, the invention relates to a method of treating apatient having solid malignancies characterized by positive FGFR4 andKLB expression comprising administering to said patient atherapeutically effective amount of a compound of the present inventionor a pharmaceutically acceptable salt thereof.

In an embodiment, the invention relates to a method of treating apatient having solid malignancies characterized by positive FGFR4 andFGF19 expression comprising administering to said patient atherapeutically effective amount of a compound of the present inventionor a pharmaceutically acceptable salt thereof.

In an embodiment, the invention relates to a method of treating apatient having solid malignancies characterized by positive FGFR4, KLBand FGF19 expression comprising administering to said patient atherapeutically effective amount of a compound of the present inventionor a pharmaceutically acceptable salt thereof.

In an embodiment, the invention relates to a method of selectivelytreating a patient having solid malignancies, comprising selectivelyadministering a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt thereof to thepatient on the basis of the patient having solid malignanciescharacterized by positive FGFR4 and KLB expression, or positive FGFR4and FGF19 expression, or positive FGFR4, KLB and FGF19 expression.

In an embodiment, the invention relates to a method of selectivelytreating a patient having solid malignancies with a compound of thepresent invention or a pharmaceutically acceptable salt thereofcomprising

-   -   a) Selecting the patient for treatment with a compound of the        present invention or a pharmaceutically acceptable salt thereof        on the basis of the patient having positive FGFR4 and KLB        expression, or positive FGFR4 and FGF19 expression, or positive        FGFR4, KLB and FGF19 expression; and    -   b) Thereafter, administering a therapeutically effective amount        of a compound of the present invention or a pharmaceutically        acceptable salt thereof to the patient.

In an embodiment, the invention relates to a method of selectivelytreating a patient having solid malignancies, comprising

-   -   a) Assaying a biological sample from the patient for FGFR4 and        KLB expression, or FGFR4 and FGF19 expression, or FGFR4, KLB and        FGF19 expression    -   b) Thereafter, selectively administering to the patient a        therapeutically effective amount of a compound of the present        invention or a pharmaceutically acceptable salt thereof on the        basis of the biological sample from the patient having positive        FGFR4 and KLB expression, or positive FGFR4 and FGF19        expression, or positive FGFR4, KLB and FGF19 expression.

In an embodiment, the invention relates to a method of selectivelytreating a patient having solid malignancies, comprising:

-   -   1) Assaying a biological sample from the patient for FGFR4 and        KLB expression, or FGFR4 and FGF19 expression, or FGFR4, KLB and        FGF19 expression;    -   2) Thereafter, selecting the patient for treatment with a        compound of the present invention on the basis of the biological        sample from the patient having positive FGFR4 and KLB        expression, or positive FGFR4 and FGF19 expression, or positive        FGFR4, KLB and FGF19 expression    -   3) Thereafter, administering a therapeutically effective amount        of a compound of the present invention or a pharmaceutically        acceptable salt thereof to the patient.

In an embodiment of the invention, the biological sample is selectedfrom blood, plasma and tissue sample. In an embodiment of the invention,the positive expression of FGF19 is assayed from a blood sample. In anembodiment of the invention, the positive expression of FGF19 is assayedfrom a tissue sample. In an embodiment of the invention, the positiveexpression of FGFR4 or KLB is assayed from a tissue sample.

The methods of the invention include detecting expression of thebiomarker gene product (i.e. FGFR4, KLB, FGF19 gene products) in asample taken from a patient having solid malignancies and can beperformed by detecting, for example, RNA transcribed from the biomarkergene such as mRNA, or polypeptides encoded by the biomarker gene. Thelevel of expression of the biomarker can be used to predict whether apatient will likely respond to a compound as described herein. Thosepatients that have an increased level of expression of the biomarkercompared to a control (referred to also herein as patients having a“positive expression of the biomarker”) are selected for treatment withthe compound described herein as it is predicted that such a patient hasan increased likelihood of responding to such compounds.

Any appropriate sample of cells taken from a patient having solidmalignancies can be used. Generally, the sample of cells or tissuesample will be obtained from the subject with solid malignancies bybiopsy or surgical resection. In some instances, the sample taken fromthe patient having solid malignancies may be a blood sample. The sampleof, for example tissue, may also be stored in, e.g., RNA later (Ambion;Austin Tex.) or flash frozen and stored at −80° C. for later use. Thebiopsied tissue sample may also be fixed with a fixative, such asformaldehyde, paraformaldehyde, or acetic acid/ethanol. The fixed tissuesample may be embedded in wax (paraffin) or a plastic resin. Theembedded tissue sample (or frozen tissue sample) may be cut into thinsections. RNA or protein may also be extracted from a fixed orwax-embedded tissue sample or a frozen tissue sample. Once a sample ofcells or sample of tissue is removed from the subject with cancer, itmay be processed for the isolation of RNA or protein using techniqueswell known in the art and as described below.

An example of extraction of RNA from a biopsy taken from a patient withsolid malignancies can include, for example, guanidium thiocyanate lysisfollowed by CsCl centrifugation (Chirgwin, et al., Biochemistry18:5294-5299, 1979). RNA from single cells may be obtained as describedin methods for preparing cDNA libraries from single cells (see, e.g.,Dulac, Curr. Top. Dev. Biol. 36:245, 1998; Jena, et al., J. Immunol.Methods 190:199, 1996). In one embodiment, the RNA population may beenriched for sequences of interest. Enrichment may be accomplished, forexample, by random hexamers and primer-specific cDNA synthesis, ormultiple rounds of linear amplification based on cDNA synthesis andtemplate-directed in vitro transcription (see, e.g., Wang, et al., Proc.Natl. Acad. Sci. USA 86:9717, 1989; Dulac, et al., supra; Jena, et al.,supra).

In one embodiment, the assaying method includes providing a nucleic acidprobe comprising a nucleotide sequence, for example, at least 10, 15, 25or 40 nucleotides, and up to all or nearly all of the coding sequencewhich is complementary to a portion of the coding sequence of a nucleicacid sequence of FGFR4, KLB and FGF19; obtaining a tissue sample from amammal having a cancerous cell; contacting the nucleic acid probe understringent conditions with RNA obtained from a biopsy taken from apatient (e.g., in a Northern blot, in situ hybridization assay, PCRetc); and determining the amount of hybridization of the probe with RNA.Nucleic acids may be labeled during or after enrichment and/oramplification of RNAs.

In the method of the invention, the step of assaying may comprise atechnique as described below. Further examples of assaying are describedin the examples.

The biomarkers FGFR4, KLB and FGF19 can be assayed using any methodknown in the art such as reverse Transcriptase PCR (RT-PCR). This methodincludes isolating mRNA using any technique known in the art, e.g., byusing a purification kit, buffer set and protease from commercialmanufacturers, such as Qiagen. The reverse transcription step istypically primed using specific primers, random hexamers, or oligo-dTprimers, depending on the circumstances and the goal of expressionprofiling and the cDNA derived can then be used as a template in thesubsequent PCR reaction. TaqMan(R) RT-PCR can then be performed using,e.g., commercially available equipment.

A more recent variation of the RT-PCR technique is the real timequantitative PCR, which measures PCR product accumulation through adual-labeled fluorigenic probe (e.g., using TaqMan® probe). Real timePCR is compatible both with quantitative competitive PCR, where internalcompetitor for each target sequence is used for normalization, and withquantitative comparative PCR using a normalization gene contained withinthe sample, or a housekeeping gene for RT-PCR. For further details see,e.g. Held et al, Genome Research 6:986-994 (1996).

In another example, microarrays are used which include one or moreprobes corresponding to one or more of genes FGFR4, KLB and FGF19. Themethod includes the production of hybridization patterns of labeledtarget nucleic acids on the array surface. The resultant hybridizationpatterns of labeled nucleic acids may be visualized or detected in avariety of ways, with the particular manner of detection selected basedon the particular label of the target nucleic acid. Representativedetection means include scintillation counting, autoradiography,fluorescence measurement, calorimetric measurement, light emissionmeasurement, light scattering, and the like.

In another example, a TaqMan® Low Density Array (TLDA) card can be usedwhich can include one or more probes corresponding to one or more ofgenes FGFR4, KLB and FGF19. This method uses a microfluidic card thatperforms simultaneous real time PCR reactions.

In one example, the method of detection utilizes an array scanner thatis commercially available (Affymetrix, Santa Clara, Calif.). The scanneris controlled from a system computer with an interface and easy-to-usesoftware tools. The output may be directly imported into or directlyread by a variety of software applications. Scanning devices aredescribed in, for example, U.S. Pat. Nos. 5,143,854 and 5,424,186.

Once the level of expression of the biomarker is assayed it can becompared to a control. A control for comparison can be determined by oneskilled in the art. In one example, a control is determined by choosingan expression value that serves as a cut-off value such that the valuedifferentiates between those test samples that have increased biomarkerexpression, positive expression, from those that do not. In anotherexample, the control can be a test sample taken from a healthy person ora sample such as a tumor sample where the biomarkers do not showexpression or do not have increased expression above a normal/basallevel.

In one example, the expression of each biomarker is measured and can beconverted into an expression value after normalization by the expressionlevel of a housekeeping gene. These expression values then can be usedto generate a score which is then compared against a cut-off to selectwhich subjects have positive biomarker expression and therefore arelikely to benefit from treatment with compound as described herein.

Alternatively, the presence of a protein product encoded by thebiomarkers can be assayed using any appropriate method known in the artand the level of protein product can be compared to a control. Exemplaryimmunoassays that may be conducted according to the invention includefluorescence polarization immunoassay (FPIA)₅ fluorescence immunoassay(FIA), enzyme immunoassay (EIA), nephelometric inhibition immunoassay(NIA), enzyme-linked immunosorbent assay (ELISA), and radioimmunoassay(RIA). An indicator moiety, or label group, may be attached to thesubject antibodies and is selected so as to meet the needs of varioususes of the method that are often dictated by the availability of assayequipment and compatible immunoassay procedures. General techniques tobe used in performing the various immunoassays noted above are known tothose of ordinary skill in the art. Alternatively, other methods can beused such as Western blot analysis that includes electrophoreticallyseparating proteins on a polyacrylamide gel, and after staining theseparated proteins, the relative amount of each protein can bequantified by assessing its optical density. Alternatively, othermethods such as dot-blot assays, FACS or immunohistochemistry can beused.

Typically, antibodies generated against the biomarkers of the inventioncan be used for visualizing for the presence of a protein of interestand can be labeled, for example, using a reporter molecule such asfluorophores, enzymes, biotin, chemiluminescent molecules,bioluminescent molecules, digoxigenin, avidin, streptavidin orradioisotopes.

Those patients that are determined to have an increased level ofbiomarker protein product compared to a control are referred to hereinas having positive biomarker expression.

In an embodiment of the invention, the solid malignancies are from acancer selected from liver cancer, breast cancer, glioblastoma, prostatecancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer,colon cancer.

In an embodiment, the invention relates to a pharmaceutical compositioncomprising a compound of the present invention or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutically acceptablecarriers for use in the treatment of solid malignancies characterized bypositive FGFR4 and KLB expression, or by positive FGFR4 and FGF19expression, or by positive FGFR4, KLB and FGF19 expression.

In an embodiment, the invention relates to a method of treating cancer,comprising selectively administering a pharmaceutical compositioncomprising a compound of the present invention or a pharmaceuticallyacceptable salt thereof to a patient in need thereof on the basis ofsaid patient having positive FGFR4 and KLB expression, or positive FGFR4and FGF19 expression, or positive FGFR4, KLB and FGF19 expression.

In an embodiment of the invention, the cancer is selected from livercancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma,gastric cancer, ovarian cancer, lung cancer, colon cancer.

In a further embodiment, the composition comprises at least twopharmaceutically acceptable carriers, such as those described herein.For purposes of the present invention, unless designated otherwise,solvates and hydrates are generally considered compositions. Preferably,pharmaceutically acceptable carriers are sterile. The pharmaceuticalcomposition can be formulated for particular routes of administrationsuch as oral administration, parenteral administration, and rectaladministration, etc. In addition, the pharmaceutical compositions of thepresent invention can be made up in a solid form (including withoutlimitation capsules, tablets, pills, granules, powders orsuppositories), or in a liquid form (including without limitationsolutions, suspensions or emulsions). The pharmaceutical compositionscan be subjected to conventional pharmaceutical operations such assterilization and/or can contain conventional inert diluents,lubricating agents, or buffering agents, as well as adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers and buffers,etc.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with one or more of:

a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine;b) lubricants, e.g., silica, talcum, stearic acid, its magnesium orcalcium salt and/or polyethyleneglycol;c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone;d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt,or effervescent mixtures; ande) absorbents, colorants, flavors and sweeteners.

In an embodiment, the pharmaceutical compositions are capsulescomprising the active ingredient only.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs, solutions or soliddispersion.

Compositions intended for oral use are prepared according to any methodknown in the art for the manufacture of pharmaceutical compositions andsuch compositions can contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations.

Tablets may contain the active ingredient in admixture with nontoxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like.

They are thus particularly suited for use in topical, includingcosmetic, formulations well-known in the art. Such may containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application.

They may be conveniently delivered in the form of a dry powder (eitheralone, as a mixture, for example a dry blend with lactose, or a mixedcomponent particle, for example with phospholipids) from a dry powderinhaler or an aerosol spray presentation from a pressurised container,pump, spray, atomizer or nebuliser, with or without the use of asuitable propellant.

The pharmaceutical composition used in the present invention can be inunit dosage of about 1-1000 mg of active ingredient(s) for a subject ofabout 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg orabout 0.5-100 mg, or about 1-50 mg of active ingredients. Thetherapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Celsius. If not mentioned otherwise, all evaporations areperformed under reduced pressure, typically between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesise thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art.

Further, the compounds of the present invention can be produced byorganic synthesis methods known to one of ordinary skill in the art asshown in the following examples.

Abbreviations Abbreviation Description aq. aqueous conc. concentratedDAST (diethylamino)sulfur trifluoride dba dibenzylideneacetone DCMdichloromethane DIPEA N,N-diisopropylethylamine,N-ethyl-N-isopropylpropan-2- amine DMA N,N-dimethylacetamide DMAP4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxideDMSO-d₆ Hexadeuterodimethyl sulfoxide dppf1,1′-bis(diphenylphosphino)ferrocene DSC Differential scanningcalorimetry ESI-MS Electrospray ionization mass spectroscopy h hour HPLCHigh-performance liquid chromatography KHMDS Potassiumhexamethyldisilazide l/ml litre/millilitre LC-MS liquid chromatographyand mass spectrometry LHMDS Lithium hexamethyldisilazide M molar minminutes mp Melting point MW microwave mw Molecular weight m/z mass tocharge ratio NBS N-bromosuccinimide NIS N-iodosuccinimide NMPN-methylpyrrolidinone, 1-methyl-2-pyrrolidinone NMR Nuclear magneticresonance org. organic RP Reverse phase sat saturated SFC Supercriticalfluid chromatography TFA trifluoroacetic acid THF tetrahydrofurane t_(R)or Rt Retention time (if not indicated, in minutes) UPLCUltra-performance liquid chromatography

Analytical Details

NMR: Measurements were performed on a Bruker Ultrashield™ 400 (400 MHz),Bruker Ultrashield™ 600 (600 MHz), 400 MHz DRX Bruker CryoProbe (400MHz) or a 500 MHz DRX Bruker CryoProbe (500 MHz) spectrometer using ornot trimethylsilane as an internal standard. Chemical shifts (d-values)are reported in ppm downfield from tetramethylsilane, spectra splittingpattern are designated as singlet (s), doublet (d), triplet (t), quartet(q), multiplet, unresolved or more overlapping signals (m), broad signal(br). Solvents are given in parentheses.DSC: DSC measurements were performed using a DSC Q2000 (TA Instruments,New Castle, Del., USA) equipped with a DSC Refrigerated Cooling System(TA Instruments, New Castle, Del., USA).

Data were treated mathematically using the resident Universal Analysis®Software. Calibration for temperature and heat of fusion was carried outwith indium as reference material. The samples were analyzed in openaluminium pans and scanned under a nitrogen purge with a heating rate of10° C./min from 20 to 300° C.

UPLC-MS 1:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity HSS T3 1.8 μm 2.1×50 mm.

Flow: 1.2 ml/min. Column temperature: 50° C.Gradient: from 2 to 98% B in 1.4 min, A=water+0.05% formic acid+3.75 mMammonium acetate, B=acetonitrile+0.04% formic acid.

UPLC-MS 3:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity HSS T3 1.8 μm 2.1×50 mm.

Flow: 1.0 ml/min. Column temperature: 60° C.Gradient: from 5 to 98% B in 1.4 min, A=water+0.05% formic acid+3.75 mMammonium acetate, B=acetonitrile+0.04% formic acid.

UPLC-MS 6:

System: Waters Acquity Ultra Performance with Waters SQ detector.

Column: Acquity HSS T3 1.8 μm 2.1×50 mm.

Flow: 1.0 ml/min. Column temperature: 60° C.Gradient: from 5 to 98% B in 1.4 min, A=water+0.05% formic acid+3.75 mMammonium acetate, B=acetonitrile+0.04% formic acid.

UPLC-MS 7:

System: Waters Acquity Ultra Performance with Waters SQ detector.

Column: Acquity HSS T3 1.8 μm 2.1×50 mm.

Flow: 1.0 ml/min. Column temperature: 60° C.Gradient: from 5 to 98% B in 1.4 min, A=water+0.05% formic acid+3.75 mMammonium acetate, B=acetonitrile+0.04% formic acid.

Preparative Methods: Flash Chromatography System: System: Teledyne ISCO,CombiFlash Rf.

Column: pre-packed RediSep® Rf cartridges.Samples were absorbed on Isolute, or on silica gel, or applied assolutions.

Supercritical Fluid Chromatography (SFC 1):

System: Waters SFC 100 prep-system with a Waters 2998 Photodiode Array(PDA) Detector and a Waters 3100 Mass detector.Column dimension: 250×30 mm.

Columns:

Manufacturer code Name Particle size Pore size Princeton PPUPropyl-pyridyl-urea 5 μm 100 Å 4EP 4 Ethylpyridine 5 μm  60 Å DEAPDiethylaminopropyl 5 μm  60 Å Reprosil NH2 Amino 5 μm 100 Å DNH Diamino5 μm 100 Å SiOH Silica 5 μm 100 Å Waters Hilic Atlantis Silica OBD 5 μm100 ÅFlow: 100 ml/min 120 bar back pressureGradient: optimized gradient elution using supercritical CO₂/MeOH.

Reversed Phase HPLC (RP 4):

System: Gilson preparative HPLC system with UV-triggered collectionsystem (254 nm).Column: Sunfire Prep C18 OBD 5 μm 30×100 cm, temperature 25° C.Gradient: gradient from 5-40% acetonitrile in water containing 0.1% TFAover 20 minutes, flow rate 30 ml/min.

Example 3:N-(5-cyanopyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

A solution ofN-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(intermediate 2, 150 mg, 0.424 mmol) in THF (3 ml) was treated withwater (2.25 ml) and HCl conc. (0.75 ml). The reaction mixture wasstirred for 15 min at room temperature. The reaction was quenched byaddition of sat. aq. NaHCO₃ (gas evolution) and extracted with DCM (3×).The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude material waspurified by normal phase chromatography (12 g silica gel cartridge,heptanes/EtOAc 100:0 to 0:100) to give the title compound as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.86 (s, 1H), 9.96 (d, 1H), 8.80 (dd, 1H),8.27 (dd, 1H), 8.22 (dd, 1H), 7.94 (d, 1H), 7.68 (d, 1H), 4.30-3.96 (m,2H), 2.95 (t, 2H), 2.03-1.90 (m, 2H).

(UPLC-MS 1) t_(R) 0.98 min; ESI-MS 308.1 [M+H]⁺.

Intermediate 2:N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

A solution of phenyl7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate(intermediate 3, 262 mg, 0.798 mmol) and 2-amino-5-cyanopyridine (190mg, 1.60 mmol) in THF (7.5 ml) at −15° C. under argon was treated dropwise with LHMDS (1 M in THF, 1.60 ml, 1.60 mmol). The reaction mixturewas stirred at −15° C. for 25 min and then quenched by addition of sat.aq. NH₄Cl and extracted with EtOAc (2×). The combined org. layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude material was purified by normal phasechromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to0:100) to give the title compound as a white solid. (UPLC-MS 1) t_(R)1.09 min; ESI-MS 354.1 [M+H]⁺.

Intermediate 3: phenyl7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

A solution of 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine(intermediate 4, 2 g, 9.60 mmol) and diphenylcarbonate (4.11 g, 19.21mmol) in THF (40 ml) at −15° C. was treated with LHMDS (1M in THF, 13.3ml, 13.3 mmol) over 0.5 h. The reaction mixture was quenched with sat.aq. NH₄Cl, extracted with EtOAc (2×). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude product was purified by normal phasechromatography (80 g silica gel cartridge, heptanes/EtOAc 100:0 to25:75) to give the title compound as a pale yellow solid. ¹H-NMR (400MHz, DMSO-d₆) δ 7.65 (d, 1H), 7.46-7.38 (m, 2H), 7.27-7.18 (m, 4H), 5.17(s, 1H), 3.87-3.80 (m, 2H), 3.26 (s, 6H), 2.83 (t, 2H), 2.00-1.92 (m,2H).

Intermediate 4: 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

The procedure described in J. Org. Chem., 2004, 69 (6), pp 1959-1966 wasused. Into a 5-1 pressure tank reactor (5 atm) was placed2-(dimethoxymethyl)-1,8-naphthyridine (intermediate 5, 200 g, 979 mmol),ethanol (3 l), PtO₂ (12 g). The reactor was evacuated and flushed threetimes with nitrogen, followed by flushing with hydrogen. The mixture wasstirred overnight at 23° C. under an atmosphere of hydrogen. Thisreaction was repeated four times. The solids were filtered out and theresulting mixture was concentrated under vacuum to give the titlecompound as a yellow solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.14 (d, 1H), 6.51 (d, 1H), 6.47-6.41 (m,1H), 4.98 (s, 1H), 3.28-3.19 (m, 2H), 3.23 (s, 6H), 2.64 (t, 2H),1.73-1.79 (m, 2H).

Intermediate 5: 2-(dimethoxymethyl)-1,8-naphthyridine

The procedure described in J. Org. Chem., 2004, 69 (6), pp 1959-1966 wasused. Into a 20 l 4-necked round-bottom flask was placed2-aminopyridine-3-carbaldehyde (1000 g, 8.19 mol),1,1-dimethoxypropan-2-one (1257 g, 10.64 mol), ethanol (10 l), and water(2 l). This was followed by the addition of a solution of sodiumhydroxide (409.8 g, 10.24 mol) in water (1000 ml) drop wise withstirring at 0-15° C. The solution was stirred for 3 h at 0-20° C. andthen concentrated under vacuum. The resulting solution was extractedwith 3×1200 ml of ethyl acetate and the organic layers were combined.The mixture was dried over sodium sulfate and concentrated under vacuum.The residue was washed with 3×300 ml of hexane and the solid wascollected by filtration. This resulted in the title compound as a yellowsolid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.11 (dd, 1H), 8.53 (d, 1H), 8.50(dd, 1H), 7.73 (d, 1H), 7.67 (dd, 1H), 5.44 (s, 1H), 3.41 (s, 6H).

Example 27:N-(5-cyanopyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

From intermediate 25, reacted in an analogous manner to the preparationof Example 18.

¹H NMR (400 MHz, DMSO-d₆) indicated a partially overlapping mixture ofthe title compound (minor) and the corresponding 5-membered ring lactol(Major) in a ˜1:3.1 ratio as determined by integration of the signals at13.93 and 13.48 ppm. Major: δ 13.48 (s, 1H), 8.77-8.74 (m, 1H),8.31-8.20 (m, 2H), 7.73 (s, 1H), 7.05 (d, 1H), 6.19 (d, 1H), 5.09-5.01(m, 1H), 4.95-4.87 (m, 1H), 4.06-3.88 (m, 2H), 2.88 (t, 2H), 2.02-1.86(m, 2H); minor: 13.93 (s, 1H), 10.09 (s, 1H), 8.82-8.78 (m, 1H),8.31-8.20 (m, 2H), 8.06-8.01 (m, 1H), 5.51 (t, 1H), 4.95-4.87 (m, 2H),4.06-3.88 (m, 2H), 2.98 (t, 2H), 2.02-1.86 (m, 2H).

(UPLC-MS 3) t_(R) 0.81, 0.86; ESI-MS 338.1, 338.1 [M+H]⁺.

Intermediate 25:N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

To a solution of6-bromo-N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(intermediate 2H, 171 mg, 0.396 mmol) in THF (5 ml) at −78° C., wasadded MeLi (1.6 M in Et₂O, 0.247 ml, 0.396 mmol), the solution wasstirred for 5 min. Then, n-BuLi (1.6 M in hexane, 0.272 ml, 0.435 mmol)was added and the solution was stirred for 20 min. Then, DMF (0.184 ml,2.37 mmol) was added. The reaction mixture was stirred at −78° C. for1.5 h and then allowed to warm to room temperature. The reaction mixturewas poured into sat. aq. NH₄Cl and extracted twice with DCM. The organicphase was then dried over Na₂SO₄, filtered and evaporated. The residuewas purified by normal phase chromatography (12 g gold silica gelcartridge, heptanes/EtOAc 100:0 to 0:100). TheN-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamidecontaining fraction were concentrated. The residue was dissolved in MeOH(1.5 ml) and DCM (1.5 ml) and treated with NaBH₄ (5.32 mg, 0.141 mmol).The reaction mixture was stirred at room temperature for 30 min, thenpoured into sat. aq. NH₄Cl and extracted with DCM (3×). The combinedorganic phases were then dried over Na₂SO₄, filtered and evaporated. Thecrude material was purified by normal phase chromatography (4 g silicagel cartridge, heptanes/EtOAc 100:0 to 0:100) followed by a reversephase chromatography (13 g C18 cartridge, 0.1% TFA in water/acetonitrile80:20 to 0:100). The product containing fractions were treated with sat.aq. Na₂CO₃, concentrated until the organic solvent had been removedextracted with DCM (3×). The combined organic layers were dried overNa₂SO₄, filtered and evaporated to give the title compound as acolorless resin. (UPLC-MS 3) t_(R) 0.92 min; ESI-MS 384.1 [M+H]⁺.

Reference Example 18:7-formyl-6-(hydroxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

A solution of7-(dimethoxymethyl)-6-(hydroxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(intermediate 14, 18 mg, 0.042 mmol) in THF (0.8 ml) was treated withwater (0.6 ml) and conc. HCl (0.2 ml) and stirred for 15 min. Thereaction mixture was quenched by addition of sat. aq. NaHCO₃ (gasevolution), extracted with DCM (3×). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude material was triturated with EtOAc/heptanes 10:1,filtered and dried under vacuum to give the title compound as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) indicated a partially overlapping mixture ofthe title compound (Minor) and the corresponding 5-membered ring lactol(Major) in a ˜1:2.1 ratio as determined by integration of the signals at13.87 and 13.38 ppm. δ Major: 13.38 (s, 1H), 8.69-8.66 (m, 1H), 8.28 (d,1H), 8.19 (td, 1H), 7.73 (s, 1H), 7.02 (d, 1H), 6.19 (dd, 1H), 5.09-5.01(m, 1H), 4.94-4.87 (m, 1H), 4.06-3.89 (m, 2H), 2.89 (t, 2H), 2.00-1.88(m, 2H); Minor: 13.87 (s, 1H), 10.11 (s, 1H), 8.75-8.72 (m, 1H), 8.28(d, 1H), 8.19 (td, 1H), 8.03 (s, 1H), 5.50 (t, 1H), 4.94-4.87 (m, 2H),4.06-3.89 (m, 2H), 2.98 (t, 2H), 2.00-1.88 (m, 2H).

(UPLC-MS 1) t_(R) 0.97, 1.05; ESI-MS 381.1, 381.1 [M+H]⁺.

Reference Intermediate 14:7-(dimethoxymethyl)-6-(hydroxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

A solution of6-bromo-7-(dimethoxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(intermediate 2D, 100 mg, 0.210 mmol) in THF (2 ml) at −78° C. underargon was treated drop wise with n-BuLi (1.5 M in hexane, 0.309 ml,0.463 mmol). The resulting brown solution was stirred for 2 min and thenDMF (0.1 ml, 1.29 mmol) was added. The resulting yellow solution wasstirred at −78° C. for 15 min. The reaction mixture was quenched byaddition of sat. aq. NH₄Cl, warmed to room temperature and extractedwith EtOAc (2×). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by normal phase chromatography (12 g silica gelcartridge, heptanes/EtOAc 100:0 to 0:100) the7-(dimethoxymethyl)-6-formyl-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamidecontaining fractions were concentrated to give a white solid. Thismaterial was dissolved in MeOH (2 ml) and DCM (1 ml), treated at roomtemperature with NaBH₄ (6.36 mg, 0.168 mmol) and stirred for 0.5 h. Thereaction mixture was quenched with sat. aq. NH₄Cl and extracted with DCM(3×). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude material was purified bynormal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc100:0 to 0:100) the product containing fractions were concentrated togive the title compound as a white solid. (UPLC-MS 1) t_(R) 1.10 min;ESI-MS 421.0 [M+H]⁺.

Reference Intermediate 2D:6-bromo-7-(dimethoxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

From intermediate 11 and 5-(trifluoromethyl)pyridin-2-amine, reacted inan analogous manner to the preparation of intermediate 2. H NMR (400MHz, DMSO-d₆) δ ppm 13.56 (s, 1H) 8.70-8.75 (m, 1H) 8.26 (d, 1H) 8.16(dd, 1H) 7.99 (s, 1H) 5.59 (s, 1H) 3.91-3.98 (m, 2H) 3.39 (s, 6H) 2.85(t, 2H) 1.86-1.96 (m, 2H).

Intermediate 11: phenyl6-bromo-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

A solution of6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine(intermediate 12, 2.28 g, 7.94 mmol) and diphenylcarbonate (2.13 g, 9.93mmol) in THF (40 ml) at −17° C. was treated drop wise over 5 min withLHMDS (1M in THF, 8.34 ml, 8.34 mmol). The yellow reaction mixture wasstirred for 30 min, quenched with sat. aq. NH₄Cl and extracted withEtOAc (2×). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudewas purified by normal phase chromatography (80 g silica gel cartridge,heptanes/EtOAc 100:0 to 0:100) to give the title compound as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (s, 1H) 7.37-7.45 (m, 2H)7.19-7.28 (m, 3H) 5.46 (s, 1H) 3.80-3.87 (m, 2H) 3.29 (s, 6H) 2.84 (t,2H) 1.90-2.00 (m, 2H).

Reference Intermediate 12:6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

Into a 3 l 4-necked round-bottom flask was placed7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate4, 114.6 g, 550.3 mmol) in acetonitrile (2 l). This was followed by theaddition of NBS (103 g, 578 mol) in portions with stirring at 25° C. Theresulting solution was stirred for 30 min at 25° C. The resultingmixture was concentrated under vacuum and the residue was diluted with1000 ml of diethylether. The mixture was washed with 3×100 ml ofice/water. The aqueous phase was extracted with 2×100 ml of diethyletherand the organic layers were combined. The resulting mixture was washedwith 1×100 ml of brine, dried over sodium sulfate and concentrated undervacuum to give the title compound as a light yellow solid. LC-MS: (ES,m/z): 286.03 [M+H]⁺. ¹H-NMR: (300 MHz, CDCl₃) δ 1.86-1.94 (2H, m),2.70-2.74 (2H, m), 3.9-3.43 (2H, m), 3.47 (6H, s), 5.23 (1H, s), 5.58(1H, s), 7.29 (1H, s).

Example 39:N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

To a solution of6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(intermediate 37, 98 mg, 0.171 mmol) in THF (1 ml) and H₂O (1 ml) wasadded conc. HCl (0.5 ml), the reaction mixture was stirred at roomtemperature for 6 h. The reaction mixture was poured into sat. aq.NaHCO₃ and extracted with DCM (2×). The organic phase was then driedover Na₂SO₄, filtered and evaporated. Trituration of the crude materialin EtOAc/heptanes followed by drying under vacuum furnished the titlecompound as a colorless powder.

¹H NMR (400 MHz, DMSO-d₆) indicated a partially overlapping mixture ofthe title compound (Minor) and the corresponding 5-membered ring lactol(Major) in a ˜1:2.8 ratio as determined by integration of the signals at13.90 and 13.42 ppm. δ Major: 13.42 (s, 1H), 8.55 (s, 1H), 7.97 (s, 1H),7.73 (s, 1H), 7.02-7.10 (m, 1H), 6.14-6.23 (m, 1H), 5.05 (dd, 1H),4.86-4.94 (m, 1H) 4.29-4.38 (m, 2H), 3.88-4.03 (m, 2H), 3.71-3.77 (m,2H), 2.88 (t, 2H), 1.86-2.00 (m, 2H). Minor: 13.90 (s, 1H), 10.07 (s,1H), 8.60 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 5.51 (t, 1H), 4.86-4.94(m, 2H), 4.29-4.38 (m, 2H), 3.88-4.03 (m, 2H), 3.71-3.77 (m, 2H), 2.98(t, 2H), 1.86-2.00 (m, 2H).

(UPLC-MS 3) t_(R) 0.87, 0.91; ESI-MS 412.2, 412.2 [M+H]⁺.

Intermediate 37:6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

To a solution of phenyl6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate(intermediate 38, 206 mg, 0.436 mmol) and6-amino-4-(2-methoxyethoxy)nicotinonitrile (intermediate 20, 93 mg,0.479 mmol) in THF (3 ml) at −78° C. was slowly added LHMDS (1 M in THF,0.959 ml, 0.959 mmol). The reaction mixture was stirred at −78° C. for30 min, then allowed to warm to room temperature. The reaction mixturewas poured into sat. aq. NH₄Cl and extracted twice with DCM. The organicphase was then dried over Na₂SO₄, filtered and evaporated. The crudematerial was purified by normal phase chromatography (12 g silica gelcartridge, heptanes/EtOAc 100:0 to 50:50) followed by reverse phasechromatography (43 g C18 cartridge, 0.1% TFA in water/acetonitrile 90:10to 0:100) to give the title compound as an off-white solid. (UPLC-MS 3)t_(R) 1.59 min; ESI-MS 572.3 [M+H]⁺.

Intermediate 38: phenyl6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

To a solution of6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine(intermediate 39, 8.49 g, 24.1 mmol) and diphenyl carbonate (5.42 g,25.3 mmol) in THF (130 ml) at −78° C. was added slowly LHMDS (1 M inTHF, 25.3 ml, 25.3 mmol). The reaction mixture was stirred at −78° C.for 30 min, then allowed to warm to room temperature. The reactionmixture was poured into sat. aq. NH₄Cl and extracted twice with DCM. Thecombined organic phases were then dried over Na₂SO₄, filtered andconcentrated. The crude material was purified by normal phasechromatography (330 g silica gel cartridge, heptanes/EtOAc 100:0 to50:50) to give the title compound as a light yellow oil. ¹H NMR (400MHz, DMSO-d₆) δ 7.68 (s, 1H), 7.37-7.45 (m, 2H), 7.19-7.27 (m, 3H), 5.17(s, 1H), 4.84 (s, 2H), 3.80-3.86 (m, 2H), 3.27 (s, 6H), 2.84 (t, 2H),1.91-2.02 (m, 2H), 0.91 (s, 9H), 0.08 (s, 6H).

Intermediate 39:6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

To a solution of(2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methanol(intermediate 40, 6.5 g, 27.3 mmol) in DCM (100 ml) and DMF (25 ml) at0° C. were added DIPEA (7.15 ml, 40.9 mmol),tert-butylchlorodimethylsilane (4.93 g, 32.7 mmol) and DMAP (0.067 g,0.546 mmol). The reaction mixture was then stirred for 1 h at roomtemperature, then poured into sat. aq. NaHCO₃ and extracted twice withDCM. The combined organic phases were dried over Na₂SO₄, filtered andevaporated. The crude material was purified by normal phasechromatography (120 g silica gel cartridge, heptanes/EtOAc 95:5 to0:100) to give the title compound as a light yellow oil which solidifiedupon standing to give an off-white powder. (UPLC-MS 3) t_(R) 1.10 min;ESI-MS 353.3 [M+H]⁺.

Intermediate 40:(2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methanol

To a solution of2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde(intermediate 41, 10 g, 38.2 mmol) in MeOH (120 ml) and DCM (60 ml) wasadded NaBH₄ (1.16 g, 30.6 mmol). The reaction mixture was stirred atroom temperature for 30 min, then slowly quenched with sat. aq. NH₄Cland concentrated until the organic solvents had been mostly removed. Theresulting mixture was extracted with DCM (4×). The combined organicphases were dried over Na₂SO₄, filtered and evaporated. The crudematerial was purified by normal phase chromatography (330 g silica gelcartridge, DCM/(DCM/MeOH 9/1) 100:0 to 45:55) to give the title compoundas a yellow oil. (UPLC-MS 3) t_(R) 0.38 min; ESI-MS 239.2 [M+H]⁺.

Intermediate 41:2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde

To a solution of6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine(intermediate 12, 15.0 g, 52.2 mmol) in THF (400 ml) at −78° C. underargon, was added MeLi (1.6 M in Et₂O, 32.6 ml, 52.2 mmol), the solutionwas stirred for 5 min, then n-BuLi (1.6 M in hexane, 35.9 ml, 57.5 mmol)was added slowly and the solution was stirred for 20 min. THF (100 ml)was added to the reaction at −78° C. Subsequently, n-BuLi (1.6 M inhexane, 49.0 ml, 78 mmol) was added and the reaction mixture was stirredfor 20 min, then again n-BuLi (1.6 M in hexane, 6.53 ml, 10.45 mmol) wasadded and the mixture was stirred for 10 min at −78° C. DMF (2.10 ml,27.2 mmol) was added and the reaction mixture was stirred at −78° C. for45 min, then it was allowed to warm to room temperature, poured intosat. aq. NH₄Cl and extracted twice with DCM. The combined organic phaseswere dried over Na₂SO₄, filtered and evaporated to give the titlecompound as an orange oil. (UPLC-MS 3) t_(R) 0.63 min; ESI-MS 237.2[M+H]⁺.

Intermediate 12:6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

Into a 3 l 4-necked round-bottom flask was placed7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate4, 114.6 g, 550.3 mmol) in acetonitrile (2 l). This was followed by theaddition of NBS (103 g, 578 mol) in portions with stirring at 25° C. Theresulting solution was stirred for 30 min at 25° C. The resultingmixture was concentrated under vacuum and the residue was diluted with1000 ml of diethylether. The mixture was washed with 3×100 ml ofice/water. The aqueous phase was extracted with 2×100 ml of diethyletherand the organic layers were combined. The resulting mixture was washedwith 1×100 ml of brine, dried over sodium sulfate and concentrated undervacuum to give the title compound as a light yellow solid. LC-MS: (ES,m/z): 286.03 [M+H]⁺. ¹H-NMR: (300 MHz, CDCl₃) δ 1.86-1.94 (2H, m),2.70-2.74 (2H, m), 3.9-3.43 (2H, m), 3.47 (6H, s), 5.23 (1H, s), 5.58(1H, s), 7.29 (1H, s).

Intermediate 20: 6-amino-4-(2-methoxyethoxy)nicotinonitrile

A solution of KHMDS in THF (1M, 48.1 ml, 48.1 mmol) was added to asolution of 2-methoxy ethanol (1.68 g, 21.88 mmol) in THF (90 ml) atroom temperature. After 2 minutes 6-amino-4-fluoronicotinonitrile(intermediate 21, 3.00 g, 21.9 mmol) was added and the reaction mixturestirred for 16 h at room temperature. The reaction mixture waspartitioned between saturated aqueous NH₄Cl and EtOAc, extracted withEtOAc (2×), the combined EtOAc layers were washed with brine, dried overMgSO₄ and evaporated. The residue was triturated with EtOAc and thetitle compound obtained by filtration as a beige solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.14 (s, 1H), 6.91 (s, br, 2H), 6.03 (s, 1H), 4.19-4.13 (m,2H), 3.34-3.28 (m, 2H), 2.51 (s, 3H).

Intermediate 21: 6-amino-4-fluoronicotinonitrile

4-fluoro-5-iodopyridin-2-amine (intermediate 22, 240 g, 1 mol), zinccyanide (125 g, 1.05 mol), zinc (13 g, 0.2 mol), Pd₂(dba)₃ (25 g, 25mmol) and dppf (55 g, 0.1 mol) in DMA (800 ml) were degassed and chargedinto the round bottom flask under nitrogen. The mixture was stirred at100° C. for 3 h. The reaction mixture was diluted with 5% NaHCO₃ (2 l),extracted with EtOAc (4×600 ml). The combined organic layers were washedwith 5% NaOH (1 l), dried over Na₂SO₄, concentrated to 700 ml. Theresulting organic phase was eluted through silica gel column with EtOAc(1.7 l). The combined organic filtrate was washed with 2 M HCl (3×800ml). The pH of the aqueous phase was adjusted to 10 with saturatedNaHCO₃. The aqueous phase was extracted whit DCM (3×500 ml). Thecombined DCM was dried over Na₂SO₄ and concentrated. The residue wasfurther purified by column chromatography (eluted with pentane: EtOAc10:1 to 3:2) followed by recrystallization from pentane/EtOAc 3/1 togive the title compound as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.40(d, 1H), 7.40 (s, 2H), 6.34 (d, 1H).

Intermediate 22: 4-fluoro-5-iodopyridin-2-amine

A suspension of 4-fluoropyridin-2-amine (336 g, 2.5 mol) and NIS (745 g,2.75 mol) in MeCN (9 l) was treated with TFA (114 g, 1 mol). Thereaction mixture was then stirred at room temperature for 8 h. Thereaction mixture was diluted with EtOAc (10 l), washed with sat. aq.Na₂S₂O₃ (2×5 l), brine (4×5 l). The combined organic layers were driedover Na₂SO₄, filtered and concentrated to get the crude product. Thecrude product was purified by recrystallization from EtOAc/pentane(1/10) to afford the title compound as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.14 (d, 1H), 6.45 (s, 2H), 6.33 (d, 1H).

Example 49:(R)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

From intermediate 37H, reacted in an analogous manner to the preparationof Example 39.

(UPLC-MS 3) t_(R) 0.85, 0.90; ESI-MS 424.2, 424.2 [M+H]⁺.

Intermediate 37H:(R)-6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

From intermediates 38 and 47, reacted in an analogous manner to thepreparation of intermediate 37. (UPLC-MS 3) t_(R) 1.59 min; ESI-MS 584.3[M+H]⁺.

Intermediate 47:(R)-6-amino-4-((tetrahydrofuran-3-yl)oxy)nicotinonitrile

(R)-tetrahydrofuran-3-ol (161 mg, 1.82 mmol) was treated at roomtemperature with KHMDS (1 M in THF, 1.09 ml, 1.09 mmol). The reactionmixture was stirred for 2 min. Then, the mixture was added to a solutionof 6-amino-4-fluoronicotinonitrile (intermediate 21, 50 mg, 0.365 mmol)in NMP (0.5 ml). The resulting dark brown solution was stirred at roomtemperature for 1 h 50 min. The reaction mixture was quenched with sat.aq. NH₄Cl and extracted 2× with EtOAc. The combined organic layers weredried over Na₂SO₄, filtered and concentrated. The crude material waspurified by normal phase chromatography (4 g silica gel cartridge,DCM/(DCM/(1 M NH₃ in MeOH) 9/1) 100:0 to 0:100) to give the titlecompound as a brown solid. (UPLC-MS 3) t_(R) 0.48 min; ESI-MS 206.1[M+H]⁺.

Example 50:(S)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

From intermediate 371, reacted in an analogous manner to the preparationof Example 39.

(UPLC-MS 3) t_(R) 0.85, 0.89; ESI-MS 424.2, 424.2 [M+H]⁺.

Intermediate 371:(S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

From intermediates 38 and 47, reacted in an analogous manner to thepreparation of intermediate 37. (UPLC-MS 3) t_(R) 1.59 min; ESI-MS 584.3[M+H]⁺.

Example 63:N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-(difluoromethyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

From intermediate 37L, reacted in an analogous manner to the preparationof Example 3.

¹H NMR (400 MHz, DMSO-d₆) δ 13.66 (s, 1H), 10.01 (s, 1H), 8.62 (s, 1H),8.17 (s, 1H), 7.94 (s, 1H), 7.57 (t, 1H), 4.33-4.39 (m, 2H), 3.97-4.05(m, 2H), 3.72-3.78 (m, 2H), 3.35 (s, 3H), 3.01 (t, 2H), 1.93-2.03 (m,2H).

(UPLC-MS 3) t_(R) 1.16; ESI-MS 432.2 [M+H]⁺.

Intermediate 37L:N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-(difluoromethyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

From intermediates 54 and 20, reacted in an analogous manner to thepreparation of intermediate 37. (UPLC-MS 3) t_(R) 1.25 min; ESI-MS 478.2[M+H]⁺.

Intermediate 54: phenyl6-(difluoromethyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

To a solution of phenyl7-(dimethoxymethyl)-6-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate(intermediate 51B, 100 mg, 0.281 mmol) in DCM (2.5 ml) was added DAST(0.185 ml, 1.40 mmol), the solution was stirred at room temperature for2 h, then DAST (0.037 ml, 0.281 mmol) was added and the reaction mixturewas stirred for 1 h. The reaction mixture was poured into sat. aq.NaHCO₃ and extracted twice with DCM. The organic phase was then driedover Na₂SO₄, filtered and evaporated. The crude material was purified bynormal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc95:5 to 50:50) to give the title compound as a yellow resin.

(UPLC-MS 3) t_(R) 1.19 min; ESI-MS 379.5 [M+H]⁺.

An alternative synthesis of phenyl6-(difluoromethyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylateis outlined below:

A solution of LHMDS in THF (1.6M, 6.64 ml, 10.63 mmol) was added dropwise to a solution of6-(difluoromethyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine(intermediate 101, 1.7 g, 6.25 mmol) and diphenylcarbonate (1.41 g, 6.57mmol) in THF (20 ml) at −78° C. The reaction mixture was stirred for 30minutes at −78° C., then for 18 h at room temperature, partitionedbetween saturated aqueous NH₄Cl and DCM, extracted DCM (2×), dried overNa₂SO₄ and evaporated. The residue was preabsorbed onto isolute andpurified by normal phase chromatography using a 40 g RediSep® silicacolumn, eluting with a gradient from heptane to 50% EtOAc in heptane.Product containing fractions were combined and evaporated to give thetitle compound as a white solid.

(UPLC-MS 7) t_(R) 1.19 min; ESI-MS 379.4 [M+H]⁺.

Intermediate 51B: phenyl7-(dimethoxymethyl)-6-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

From intermediate 41 reacted in an analogous manner to the preparationof intermediate 51.

(UPLC-MS 3) t_(R) 1.08 min; ESI-MS 357.2 [M+H]⁺.

Reference Intermediate 51: phenyl7-(dimethoxymethyl)-6-iodo-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

A solution of7-(dimethoxymethyl)-6-iodo-1,2,3,4-tetrahydro-1,8-naphthyridine(intermediate 52, 97 mg, 0.290 mmol) and diphenyl carbonate (74.6 mg,0.348 mmol) in THF (2.5 ml) at −78° C. was treated with LHMDS (1 M inTHF, 0.334 ml, 0.334 mmol) and stirred for 2 h. The reaction was thenallowed to warm to room temperature over 20 min, quenched by addition ofsat. aq. NH₄Cl and extracted with DCM (2×). The organic layer was driedover Na₂SO₄, filtered and concentrated. The crude material was purifiedby normal phase chromatography (12 g silica gel cartridge,heptanes/EtOAc 100:0 to 0:100) to give the title compound as a whitesolid. (UPLC-MS 3) t_(R) 1.19 min; ESI-MS 455.1 [M+H]⁺.

Reference Intermediate 52:7-(dimethoxymethyl)-6-iodo-1,2,3,4-tetrahydro-1,8-naphthyridine

A solution of 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine(intermediate 4, 1 g, 4.8 mmol) in MeCN (15 ml) was treated with NIS(1.13 g, 5.04 mmol), stirred for 4 h in a flask covered with aluminumfoil. Them, the reaction mixture was concentrated. The residue wastreated with Et₂O and DCM, washed with water (2×) and brine, dried overNa₂SO₄, filtered and concentrated. The crude material was purified bynormal phase chromatography (80 g silica gel cartridge, heptanes/EtOAc100:0 to 0:100) to give the title compound as a yellow oil. (UPLC-MS 3)t_(R) 0.73 min; ESI-MS 335.3 [M+H]⁺.

Example 68:N-(5-cyanopyridin-2-yl)-7-formyl-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

From intermediate 59, reacted in an analogous manner to the preparationof Example 3.

¹H NMR (400 MHz, DMSO-d₆) δ 13.91 (s, 0.75H), 13.89 (s, 0.25H), 10.12(s, 0.75H), 10.09 (s, 0.25H), 8.85-8.78 (m, 1H), 8.31-8.19 (m, 2H), 7.58(s, 0.75H), 7.55 (s, 0.25H), 4.95 (s, 0.5H), 4.87 (s, 1.5H), 4.04-3.94(m, 2H), 3.02-2.91 (m, 4.25H), 2.83 (s, 0.75H), 2.12 (s, 2.25H),2.00-1.89 (m, 2.75H). 3:1 mixture of romaters.

(UPLC-MS 3) t_(R) 0.91; ESI-MS 393.2 [M+H]⁺.

Intermediate 59:N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

To a solution ofN-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-((methylamino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(intermediate 60, 14.5 mg, 0.037 mmol) in DCM (0.5 ml) was added Et₃N(10.2 μl, 0.073 mmol) and acetic anhydride (6.9 μl, 0.073 mmol). Thereaction mixture was stirred at room temperature for 30 min, poured intosat. aq. NaHCO₃ and extracted with DCM (2×). The organic phase was thendried over Na₂SO₄, filtered and concentrated. The crude material waspurified by normal phase chromatography (4 g silica gel cartridge,DCM/(DCM/MeOH 9/1) 100:0 to 0:100) to give the title compound as anoff-white solid. (UPLC-MS 3) t_(R) 0.98 min; ESI-MS 439.3 [M+H]⁺.

Intermediate 60:N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-((methylamino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

A tube was charged with methylamine hydrochloride (7.79 mg, 0.115 mmol)followed by methylamine (2 M in MeOH, 0.058 ml, 0.115 mmol) and NaCNBH₃(14.5 mg, 0.231 mmol). Then, a suspension ofN-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(intermediate 36, 22 mg, 0.058 mmol) in MeOH (1 ml) was added, the tubewas sealed and the reaction mixture was stirred at 70° C. for 1 h. Thereaction mixture was quenched with water and concentrated until theorganic solvents had mostly been removed. Water was added and themixture was extracted with DCM (3×). The organic phase was then driedover Na₂SO₄, filtered and evaporated. The crude material was purified bynormal phase chromatography (4 g silica gel cartridge, DCM/(DCM/(7 M NH₃in MeOH) 9/1) 100:0 to 50:50) to give the title compound as a yellowresin. (UPLC-MS 3) t_(R) 0.72 min; ESI-MS 397.3 [M+H]⁺.

Intermediate 36:N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

To a solution of6-bromo-N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(intermediate 2H, 300 mg, 0.694 mmol) in THF (10 ml) at −78° C., wasadded MeLi (1.6 M in Et₂O, 0.434 ml, 0.694 mmol), the solution wasstirred for 5 min, then n-BuLi in (1.6 M in hexane, 0.477 ml, 0.763mmol) was added and the solution was stirred for 20 min. Then, DMF(0.322 ml, 4.16 mmol) was added, the reaction mixture was stirred at−78° C. for 1 h and then allowed to warm to room temperature. Thereaction mixture was poured into sat. aq. NH₄Cl and extracted twice withDCM. The combined organic phase was then dried over Na₂SO₄, filtered andevaporated. The crude material was purified by normal phasechromatography (40 g gold silica gel cartridge, heptanes/EtOAc 95:5 to0:100) to give the title compound as a colorless powder.

(UPLC-MS 3) t_(R) 1.10 min; ESI-MS 382.2 [M+H]⁺.

Intermediate 2H:6-bromo-N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

From intermediate 11 and 2-amino-5-cyanopyridine, reacted in ananalogous manner to the preparation of intermediate 2. (UPLC-MS 1) t_(R)1.18 min, ESI-MS 432.0, 434.0 [M+H]⁺.

Example 80:N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

A solution of6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(intermediate 74, 3.10 g, 5.43 mmol) in THF (40 ml) was treated with H₂O(30 ml) followed by dropwise addition of conc. HCl (10 ml) and stirredfor 40 min. The reaction mixture was quenched by addition of sat. aq.NaHCO₃ (gas evolution) and then extracted with DCM (3×). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue wastreated with EtOAc (25 ml) and sonicated until a white suspension wasobtained. Then, heptanes (25 ml) was added and the resulting suspensionwas filtered. The solid was washed with heptanes and dried under vacuumto give the title compound as a white solid.

¹H NMR (400 MHz, DMSO-d₆) indicated a partially overlapping mixture ofthe title compound (Minor) and the corresponding 5-membered ring lactol(Major) in a ˜1:2.5 ratio as determined by integration of the signals at13.52 and 13.01 ppm. δ Major: 13.01 (s, 1H), 8.22 (s, 1H), 7.70 (s, 1H),7.54 (s, 1H), 7.01 (d, 1H), 6.91 (t, 1H), 6.16 (dd, 1H), 5.04 (dd, 1H),4.92-4.85 (m, 1H), 4.01-3.87 (m, 2H), 3.56-3.50 (m, 2H), 3.43-3.35 (m,2H), 3.30-3.28 (m, 3H), 2.87 (t, 2H), 2.00-1.83 (m, 2H); Minor: 13.52(s, 1H), 10.05 (s, 1H), 8.26 (s, 1H), 8.02 (s, 1H), 7.52 (s, 1H), 6.96(t, 1H), 5.47 (t, 1H), 4.92-4.85 (m, 2H), 4.01-3.87 (m, 2H), 3.56-3.50(m, 2H), 3.43-3.35 (m, 2H), 3.30-3.28 (m, 3H), 2.96 (t, 2H), 2.00-1.83(m, 2H).

(UPLC-MS 3) t_(R) 0.82, ESI-MS 411.2, [M+H]⁺.

Intermediate 74:6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

A solution of phenyl6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate(intermediate 38, 2.98 g, 6.29 mmol) and6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 1.10g, 5.72 mmol) in THF (45 ml) at −70° C. (dry ice/2-PrOH bath, internaltemperature) under argon was treated with LHMDS (1 M in THF, 12.6 ml,12.6 mmol). The resulting solution was stirred with cooling for 35 min.The cooling bath was then removed and the reaction mixture was allowedto warm to −25° C., before being re-cooled to −70° C. The resultingsolution was quenched with sat. aq. NH₄Cl, allowed to warm to roomtemperature and extracted twice with EtOAc/heptanes 1:1. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude material was purified bynormal phase chromatography (80 g silica gel cartridge, heptanes/EtOAc100:0 to 0:100). The product containing fractions were concentrated anddried under vacuum to give the title compound as a white solid. (UPLC-MS3) t_(R) 1.60; ESI-MS 571.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃-d) 6 13.81(s, 1H), 8.23 (s, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 5.45 (s, 1H), 5.26(br s, 1H), 4.87 (s, 2H), 4.07-3.99 (m, 2H), 3.63 (t, 2H), 3.52-3.38 (m,11H), 2.86 (t, 2H), 2.05-1.94 (m, 2H), 0.95 (s, 9H), 0.12 (s, 6H).

Intermediate 75: 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile

A solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 1.10 g,8.02 mmol) in DMA (20 ml) was treated with 2-methoxyethylamine (2.07 ml,24.1 mmol) and DIPEA (4.20 mL, 24.1 mmol), heated to 50° C. and stirredfor 15 h. The reaction mixture was cooled to room temperature andconcentrated. The crude material was purified by normal phasechromatography (24 g silica gel cartridge, heptanes/EtOAc 100:0 to0:100). The product containing fractions were concentrated and driedunder vacuum to give the title compound as an off-white solid.

An alternative synthesis of6-amino-4-((2-methoxyethyl)amino)nicotinonitrile is outlined below:

To tert-butyl N-{5-cyano-4-[(2-methoxyethyl)amino]pyridin-2-yl}carbamate(intermediate 287, 7 g) was added 30-36% aqueous HCl (40 ml), themixture stirred at room temperature for 30 minutes and monitored bychromatography until complete conversion. The solution was then basifiedwith 20-30% NaOH solution to pH=9-10 and filtered to give a white solid.The solid was added to ethyl acetate (15 ml) and heated to 50-55° C. toform a clear solution. The solution was then cooled to 3-6° C., stirredfor 2-3 h and filtered. The wet cake was then dried to give the titlecompound as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (s, 1H),6.39 (s, 2H), 6.15 (t, 1H), 5.61 (s, 1H), 3.46 (t, 2H), 3.27 (s, 3H),3.24 (q, 2H). (UPLC-MS 3) t_(R) 0.62; ESI-MS 193.1 [M+H]⁺.

Example 83:N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

Concentrated hydrochloric acid (0.40 ml) was added to a solution ofN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(intermediate 80, 470 mg, 0.808 mmol) in THF (3 ml) and water (1 ml) atroom temperature. After stirring for 3 h at room temperature saturatedaqueous NaHCO₃ was added, the mixture extracted with DCM (3×), theorganic layers dried over Na₂SO₄ and evaporated. The residue wassonicated with EtOAc (6 ml) and pentane (6 ml) and then filtered. Thewhite solid obtained was then dissolved in DCM (6 ml), EtOAc added (3ml), the solution warmed, sealed and allowed to stand at roomtemperature for 2 h. Filtration and drying gave the title compound as awhite solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.43 (s, 1H), 10.06 (s, 1H), 8.24 (s, 1H),7.49 (s, 1H), 7.47 (s, 1H), 6.96 (t, br, 1H), 4.86 (s, 2H), 3.96-3.90(m, 2H), 3.52-3.46 (m, 2H), 3.39-3.33 (m, 2H), 3.30-3.21 (m, 2H), 3.37(s, 3H), 3.02 (s, 2H), 2.93-2.86 (m, 2H), 2.61-2.56 (m, 2H), 2.21 (s,3H), 1.95-1.85 (m, 2H).

(UPLC-MS 6) t_(R) 0.70, ESI-MS 507.2, [M+H]⁺.

The following salts were prepared from the above free base form ofN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideby precipitation with the appropriate counterions.

Malate with 1:1 stoichiometry (mw 640.66), mp (DSC) 181.1° C. (onset):Acetone (2 ml) was added to a mixture of malic acid (26.4 mg, 0.197mmol) andN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(100 mg, 0.197 mmol) and the mixture heated on a mini-block withheating-cooling cycles from 55 to 5° C. for 7 repeat cycles (heatingrate: 1.5° C./min, cooling rate: 0.25° C./min). The white solid wascollected by centrifugation and dried for 18 h at 40° C. to give thetitle salt.

Tartrate with 1:0.5 stoichiometry (mw 581.72), mp (DSC) 176.7° C.(onset). A solution of tartaric acid (75.7 mg) in methanol (5 ml) wasprepared at room temperature (0.1 M). A portion of the 0.1 M tartaricacid in acetone solution (2 ml) was then added to a suspension ofN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(100 mg) in methanol (4 ml) and the mixture sonicated for 1 minute thenheated at 55° C. with stirring for 2 h. The white solid was thencollected by filtration, washing 2× with methanol (2 ml), and dried for18 h at 40° C. under vacuum to give the title salt.

Tartrate with 1:1 stoichiometry (mw 656.66), mp (DSC) 169.9° C. (onset):A solution of tartaric acid (75.7 mg) in acetone (5 ml) was prepared atroom temperature (0.1 M). A portion of the 0.1 M tartaric acid inacetone solution (2 ml) was then added to a suspension ofN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(100 mg) in methanol (4 ml) and the mixture sonicated for 1 minute thenheated at 55° C. with stirring for 2 h. The white solid was thencollected by filtration, washing 2× with acetone (2 ml), and dried for18 h at 40° C. under vacuum to give the title salt.

Citrate with 1:0.5 stoichiometry (mw 602.73), mp (DSC) 168.4° C.(onset): A solution of citric acid (96.9 mg) in acetone (5 ml) wasprepared at room temperature (0.1 M). A portion of the 0.1 M citric acidin acetone solution (2 ml) was then added to a suspension ofN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(100 mg) in methanol (4 ml) and the mixture sonicated for 1 minute thenheated at 55° C. with stirring for 2 h. The white solid was thencollected by filtration, washing 2× with acetone (2 ml), and dried for18 h at 40° C. under vacuum to give the title salt.

Citrate with 1:1 stoichiometry (mw 698.70), mp (DSC) 168.8° C. (onset):A solution of citric acid (96.9 mg) in acetone (5 ml) was prepared atroom temperature (0.1 M). A portion of the 0.1 M citric acid in acetonesolution (2 ml) was then added to a suspension ofN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(100 mg) in acetone (4 ml) and the mixture sonicated for 1 minute thenheated at 55° C. with stirring for 2 h before slowly cooling to roomtemperature. The white solid was then collected by filtration, washing2× with acetone (2 ml), and dried for 18 h at 40° C. under vacuum togive the title salt.

Alternatively,N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(6.5 g, 12.83 mmol) was placed in a 500 ml 4-flask reactor. 49 ml ofglacial acetic acid was added and the resulting suspension was stirredat 23° C. until a clear mixture was obtained. In a separate flask,anhydrous 2-hydroxypropane-1,2,3-tricarboxylic acid (2.59 g, 13.47 mmol,1.05 equiv.) was dissolved in 49 ml of glacial acetic acid at 50° C.until a clear solution was obtained. This solution was then added at 23°C. to theN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamidesolution previously prepared. This mixture was stirred for 30 min at 23°C. and then added dropwise over 1 h to 192 ml of ethyl acetate warmed to75° C. The temperature remained constant over the addition. At the endof the addition, the temperature of the mixture was cooled slowly to 23°C. and let 16 h at this temperature under gentle stirring. Thesuspension was cooled to 5-10° C. and filtered. The cake was washed with15 ml of ethyl acetate and 15 ml of acetone. The wet cake (ca 8.5 g) wastransferred in a 500 ml flask containing 192 ml of dry acetone. Theresulting suspension was refluxed for 24 h. The suspension was filteredand the cake was washed with 2 times 15 ml of dry acetone then dried at50° C. under vacuum for several hours to give the title salt.

Intermediate 80:N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

A solution of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile(intermediate 75, 481 mg, 2.50 mmol) in anhydrous DMF (1.5 ml) was addeddrop wise over 10 minutes to a mixture ofdi(1H-1,2,4-triazol-1-yl)methanone (410 mg, 2.50 mmol) and DMF (1.5 ml)cooled at 0° C. After stirring for 45 minutes at 0° C. the reactionmixture was allowed to warm to room temperature and after a further 90minutes at room temperature a solution of1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one(intermediate 81, 418 mg, 1.00 mmol) in DMF (2 ml) was added. Thereaction mixture was stirred for 17.5 h at room temperature, quenched bythe addition of MeOH and evaporated. The residue was applied to a 80 gRediSep® silica column as a DCM solution and purified by normal phasechromatography, eluting with a gradient from DCM to 2% MeOH in DCM.Product containing fractions were combined and evaporated to give thetitle compound as an orange foam. ¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s,1H), 8.27 (s, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 6.93 (t, 1H), 5.45 (s,1H), 4.65 (s, 2H), 3.94-3.89 (m, 2H), 3.54-3.50 (m, 2H), 3.40-3.35 (m,2H), 3.38 (s, 6H), 3.29 (s, 3H), 3.20-3.16 (m, 2H), 3.05 (s, 2H),2.86-2.80 (m, 2H), 2.61-2.55 (m, 2H), 2.22 (s, 3H), 1.94-1.88 (m, 2H).(UPLC-MS 6) t_(R) 0.72; ESI-MS 553.3 [M+H]⁺.

Example 92:N-(5-cyano-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

Concentrated hydrochloric acid (0.15 ml) was added to a solution ofN-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(intermediate 95, 188 mg, 0.301 mmol) in THF (1.1 ml) and water (0.4 ml)at room temperature. After stirring for 4 h at room temperature thereaction was assessed to be complete by HPLC/MS and saturated aqueousNaHCO₃ was added, the mixture extracted with DCM (3×), the organiclayers dried over Na₂SO₄ and evaporated. The crude residue was sonicatedwith EtOAc (6 ml) and pentane (6 ml) and then filtered. The white solidobtained was then heated and sonicated with EtOAc added (3 ml).Filtration of the cooled suspension and drying gave the title compoundas a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.78 (s, 1H), 10.09 (s, 1H), 8.55 (s, 1H),7.91 (s, 1H), 7.52 (s, 1H), 4.86 (s, 2H), 4.83 (septet, 1H), 3.99-3.95(m, 2H), 3.30-3.25 (m, 2H), 3.04 (s, 2H), 2.94-2.90 (m, 2H), 2.61-2.56(m, 2H), 2.21 (s, 3H), 1.96-1.88 (m, 2H), 1.36 (d, 6H).

(UPLC-MS 6) recorded in MeOH, t_(R) 0.83 and 0.88, ESI-MS 492.3 and534.3, [M+H]⁺ and [M+MeOH+H]⁺.

The following salts were prepared from the above free base form ofN-(5-cyano-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideby precipitation with the appropriate counterions.

Tartrate salt with 1:1 stoichiometry (mw 641.63): A solution ofL-(+)-tartaric acid in acetone (0.1 M, 2.03 ml, 0.203 mmol) was added toa suspension ofN-(5-cyano-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(100 mg, 0.203 mmol) in acetone (5 ml) at room temperature. The mixturewas warmed to 55° C., maintained at this temperature for 3 h and cooledslowly to room temperature. The white precipitate that formed was washedwith acetone and dried to give the title compound.

¹H NMR (600 MHz, DMSO-d₆) δ 13.80 (s, 1H), 10.11 (s, 1H), 8.59 (s, 1H),7.95 (s, 1H), 7.56 (s, 1H), 4.91 (s, 2H), 4.86 (septet, 1H), 4.30 (s,2H), 4.00-3.95 (m, 2H), 3.31-3.26 (m, 2H), 3.08 (s, 2H), 2.96-2.91 (m,2H), 2.67-2.62 (m, 2H), 2.26 (s, 3H), 1.97-1.89 (m, 2H), 1.40 (d, 6H).

Tosylate salt with 1:1 stoichiometry (mw 663.75): A solution of tosicacid in acetone (0.1 M, 2.03 ml, 0.203 mmol) was added to a suspensionofN-(5-cyano-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(100 mg, 0.203 mmol) in acetone (5 ml) at room temperature. The mixturewas warmed to 55° C., maintained at this temperature for 3 h and cooledslowly to room temperature. The solution was allowed to stand open tothe air for 18 h and the precipitate that formed was washed with acetoneand dried to give the title compound. H NMR (600 MHz, DMSO-d₆) δ 13.81(s, 1H), 10.10 (s, 1H), 8.59 (s, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.48(d, 2H), 7.12 (d, 2H), 4.97 (s, 2H), 4.86 (septet, 1H), 4.02-3.98 (m,2H), 3.58-3.53 (br, m, 2H), 3.41 (br, s, 2H), 2.96-2.92 (m, 2H), 2.91(br, s, 2H), 2.51 (s, 3H), 2.29 (s, 3H), 1.98-1.90 (m, 2H), 1.41 (d,6H).

Citrate salt with 1:1 stoichiometry (mw 683.68): A solution of citricacid in acetone (0.1 M, 2.03 ml, 0.203 mmol) was added to a suspensionofN-(5-cyano-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(100 mg, 0.203 mmol) in DCM (2 ml) at room temperature. The mixture waswarmed with a bath at 65° C., maintained at this temperature for 10 minand slowly cooled to 5° C. The white precipitate that formed wascollected, acetone (5 ml) and EtOH (1 ml) were added and the mixtureheated at 50° C. for 3 h. The mixture was cooled to 5° C., filtered anddried to give the title compound.

¹H NMR (600 MHz, DMSO-d₆) δ 13.82 (s, 1H), 10.11 (s, 1H), 8.59 (s, 1H),7.95 (s, 1H), 7.57 (s, 1H), 4.91 (s, 2H), 4.86 (septet, 1H), 4.01-3.97(m, 2H), 3.33-3.28 (m, 2H), 3.14 (s, 2H), 2.97-2.93 (m, 2H), 2.74 (d,2H), 2.72-2.67 (m, 2H), 2.65 (d, 2H), 2.30 (s, 3H), 1.99-1.91 (m, 2H),1.40 (d, 6H).

Intermediate 95:N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

A mixture of1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one(intermediate 81, 268 mg, 0.641 mmol), phenyl(5-cyano-4-isopropoxypyridin-2-yl)carbamate (intermediate 96, 834 mg,1.122 mmol) and DMAP (7.83 mg, 0.064 mmol) in acetonitrile (2.6 ml) washeated at reflux for 3.5 h. The reaction mixture was evaporated andapplied to a 24 g RediSep silica column as a DCM solution and purifiedby normal phase chromatography, eluting with a gradient from DCM to 10%MeOH in DCM. Product containing fractions were combined and evaporatedto give the title compound as an off-white solid.

(UPLC-MS 6) t_(R) 0.92; ESI-MS 538.7 [M+H]⁺.

Intermediate 96: phenyl (5-cyano-4-isopropoxypyridin-2-yl)carbamate

Phenyl chloroformate (3.89 ml, 31.0 mmol) was added drop wise to amixture of 6-amino-4-isopropoxynicotinonitrile (intermediate 97, 2.5 g,14.11 mmol) and pyridine (2.51 ml, 31.0 mmol) in THF (100 ml) at roomtemperature. The reaction mixture was stirred for 12 h at roomtemperature, additional pyridine (2.51 ml, 31.0 mmol) added, beforestirring for an additional 12 h and then partitioned between EtOAc andsaturated aqueous NaHCO₃ solution. The organic layer was washed withsaturated brine, dried over MgSO₄ and evaporated. The residue wastriturated with Et₂O and the product obtained by filtration as a beigesolid. (UPLC-MS 7) t_(R) 1.09; ESI-MS 298.2 [M+H]⁺.

Intermediate 97: 6-amino-4-isopropoxynicotinonitrile

A solution of KHMDS (87 g, 438 mmol) was added portionwise to a solutionof propan-2-ol (26.3 g, 438 mmol) in THF (250 ml) at room temperature.After 15 min a solution of 6-amino-4-fluoronicotinonitrile (intermediate21, 30 g, 219 mmol) in THF (200 ml) was added and the reaction mixturestirred for 18 h at room temperature. The reaction mixture waspartitioned between saturated aqueous NH₄Cl and EtOAc, extracted withEtOAc (2×), the combined EtOAc layers were dried over Na₂SO₄ andevaporated. The residue was triturated with Et₂O and the productobtained by filtration as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.12 (s, 1H), 6.82 (s, 2H), 6.07 (s, 1H), 4.64 (septet, 1H), 1.31 (d,6H). (UPLC-MS 7) t_(R) 0.61; ESI-MS 178.1 [M+H]⁺.

Intermediate 81:1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one

Sodium triacetoxyborohydride (3.10 g, 14.61 mmol) was added to a mixtureof2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde(intermediate 41, 2.30 g, 9.74 mmol), ethyl2-((2-aminoethyl)(methyl)amino)acetate dihydrochloride (intermediate 82,2.6 g, 14.61 mmol) and triethylamine (6.75 ml, 48.7 mmol) in1,2-dichloroethane (20 ml) at room temperature. The reaction mixture wasstirred for 21 h at room temperature and additional sodiumtriacetoxyborohydride (2.6 g, 9.74 mmol) was added. After a further 4 hstirring at room temperature, again additional sodiumtriacetoxyborohydride (1.3 g, 4.87 mmol) was added and the reactionmaintained at 4° C. for 2.5 days. The reaction mixture was then warmedto room temperature, saturated aqueous NaHCO₃ solution added, themixture extracted with DCM (3×), the combined organic layers dried overNa₂SO₄ and evaporated. The residue was applied to a 120 g RediSep®silica column as a DCM solution and purified by normal phasechromatography, eluting with a gradient from DCM to 10% MeOH in DCM.Product containing fractions were combined and evaporated to give thetitle compound as an orange foam. ¹H NMR (400 MHz, CDCl₃) δ 7.08 (s,1H), 5.30 (s, br, 1H), 5.20 (s, 1H), 4.69 (s, 2H), 3.44-3.34 (m, 2H),3.40 (s, 6H), 3.22-3.15 (m, 2H), 3.24 (s, 2H), 2.71-2.64 (m, 2H),2.58-2.50 (m, 2H), 2.31 (s, 3H), 1.98-1.82 (m, 2H).

(UPLC-MS 6) t_(R) 0.33; ESI-MS 335.3 [M+H]⁺.

Intermediate 82: ethyl 2-((2-aminoethyl)(methyl)amino)acetatedihydrochloride

Concentrated hydrochloric acid (10 ml) was added to a solution of ethyl2-((2-((tert-butoxycarbonyl)amino)ethyl)(methyl)amino)acetate(intermediate 83, 3.05 g, 11.13 mmol) in THF (20 ml) and EtOH (100 ml)at room temperature. After stirring 1 h at room temperature the reactionmixture was evaporated, ethanol (20 ml) added, evaporated, furtherethanol (50 ml) added and then stirred at 60° C. for 70 min. The cooledreaction mixture was then evaporated to give the title compound as apale-yellow glass. ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (s, br, 3H), 4.19(q, 2H), 4.26-4.15 (m, 2H), 3.44 (s, br, 2H), 3.21 (s, br, 2H), 2.88 (s,3H), 1.21 (t, 3H).

Intermediate 83: ethyl2-((2-((tert-butoxycarbonyl)amino)ethyl)(methyl)amino)acetate

Ethyl bromoacetate (1.27 ml, 11.48 mmol) was added to a mixture oftert-butyl (2-(methylamino)ethyl)carbamate (2.0 g, 11.48 mmol),triethylamine (4.81 ml) and THF (24 ml) at 0° C. After stirring 24 h atroom temperature the reaction mixture was partitioned between saturatedaqueous NaHCO₃ and DCM, extracted 2× with DCM, the organic layers driedover Na₂SO₄ and evaporated to give the title compound as a clearpale-yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 5.20 (s, br, 1H), 4.18 (q,2H), 3.24 (s, 2H), 3.22-3.16 (m, 2H), 2.65-2.61 (m, 2H), 2.38 (s, 3H),1.42 (s, 9H), 1.24 (t, 3H).

Example 101:N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

Hydrochloric acid (4M, 8.6 ml) was added to a solution ofN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-(dimethoxymethyl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(intermediate 107, 950 mg, 1.72 mmol) in THF (15 ml) at roomtemperature.

After stirring for 4 h at room temperature saturated aqueous NaHCO₃ wasadded, the mixture extracted with DCM (3×), the organic layers driedover MgSO₄ and evaporated. The residue was stirred with EtOAc for 20minutes then diluted with heptane and then filtered to give the titlecompound as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.83 (s, 1H), 10.11 (s, 1H), 8.60 (s, 1H),7.94 (s, 1H), 7.56 (s, 1H), 4.90 (s, 2H), 4.38-4.32 (m, 2H), 4.01-3.95(m, 2H), 3.79-3.73 (m, 2H), 3.35 (s, 3H), 3.29-3.23 (m, 2H), 3.06 (s,2H), 2.97-2.91 (m, 2H), 2.65-2.59 (m, 2H), 2.24 (s, 3H), 1.98-1.92 (m,2H).

(UPLC-MS 6) t_(R) 0.81 min, ESI-MS 508.2, [M+H]⁺.

The following salts were prepared from the above free base form ofN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideby precipitation with the appropriate counterions.

Malate with 1:1 stoichiometry (mw 641.63): A solution of L-malic acid(39.6 mg, 0.296 mmol) in acetone (3 ml) was added dropwise to a solutionofN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(150 mg, 0.296 mmol) in acetone (2 ml) at room temperature and themixture then heated at reflux for 30 minutes. The cooled mixture wasleft open to the atmosphere until the volume reduced to 3 ml then sealedand stood 18 h at 4° C. The solid was then collected by filtration,washing with Et₂O, and dried for 18 h at 40° C. under vacuum to give thetitle salt as a beige solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.78 (s, 1H), 10.06 (s, 1H), 8.58 (s, 1H),7.89 (s, 1H), 7.54 (s, 1H), 4.84 (s, 2H), 4.33-4.26 (m, 2H), 4.20 (t,1H). 3.98-3.92 (m, 2H), 3.75-3.66 (m, 2H), 3.31 (s, 3H), 3.26-3.22 (m,2H), 3.08 (s, 2H), 2.92-2.85 (m, 2H), 2.63-2.51 (m, 3H), 2.42-2.36 (m,1H), 2.21 (s, 3H), 2.03 (s, 1H), 1.96-1.88 (m, 2H).

Tosylate with 1:1 stoichiometry (mw 679.75): A solution of para-toluenesulphonic acid (49.1 mg, 0.258 mmol) in acetone (3 ml) was addeddropwise to a solution ofN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(131 mg, 0.258 mmol) in dichloromethane (5 ml) at to room temperature.After the addition was complete additional dichloromethane (3 ml) wasadded and the mixture stirred for 5 h at room temperature. The whitesolid was then collected by filtration, washing with acetone, and driedfor 18 h at 40° C. under vacuum to give the title salt.

¹H NMR (400 MHz, DMSO-d₆) δ 13.78 (s, 1H), 10.06 (s, 1H), 8.57 (s, 1H),7.91 (s, 1H), 7.54 (s, 1H), 7.45 (d, 2H), 7.07 (d, 2H), 4.92 (s, 2H),4.36-4.30 (m, 2H), 4.00-3.95 (m, 3H), 3.76-3.67 (m, 2H), 3.53-3.48 (s,br, 2H), 3.34-3.23 (m, 8H), 2.92-2.85 (m, 4H), 2.23 (s, 3H), 1.97-1.90(m, 2H).

Tartrate with 1:1 stoichiometry (mw 657.63): A solution ofL-(+)-tartaric acid (44 mg, 0.296 mmol) in acetone (5 ml) was added to asuspension ofN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(150 mg, 0.296 mmol) in acetone (5 ml) at room temperature. The mixturewas stirred at 50° C. for 30 min, decanted to remove a small amount ofinsoluble material and cooled slowly to room temperature. Theprecipitate was collected by filtration and dried under vacuum at 50° C.to give the title compound as a beige solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.78 (s, 1H), 10.09 (s, 1H), 8.57 (s, 1H),7.91 (s, 1H), 7.54 (s, 1H), 4.85 (s, 2H), 4.33-4.26 (m, 2H), 4.25 (s,2H), 3.98-3.92 (m, 2H), 3.75-3.66 (m, 2H), 3.31 (s, 3H), 3.27-3.23 (m,2H), 3.08 (s, 2H), 2.92-2.85 (m, 2H), 2.63-2.59 (m, 2H), 2.22 (s, 3H),1.96-1.88 (m, 2H).

Citrate salt with 1:1 stoichiometry (mw 699.68): A solution of citricacid (0.1 M, 1.97 ml, 0.197 mmol) was added to a suspension ofN-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(100 mg, 0.197 mmol) in acetone (5 ml) at room temperature. The mixturewas stirred at 55° C. for 3 h, cooled slowly to room temperature, thewhite precipitate collected by filtration and dried under vacuum to givethe title compound.

¹H NMR (600 MHz, DMSO-d₆) δ 13.84 (s, 1H), 10.11 (s, 1H), 8.60 (s, 1H),7.94 (s, 1H), 7.57 (s, 1H), 4.91 (s, 2H), 4.38-4.32 (m, 2H), 4.02-3.96(m, 2H), 3.79-3.73 (m, 2H), 3.36 (s, 3H), 3.31-3.25 (m, 2H), 3.14 (s,2H), 2.98-2.92 (m, 2H), 2.74 (d, 2H), 2.73-2.68 (m, 2H), 2.65 (d, 2H),2.30 (s, 3H), 1.99-1.93 (m, 2H).

Intermediate 107:N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-(dimethoxymethyl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

A mixture of1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one(intermediate 81, 1.03 g, 3.08 mmol), phenyl(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)carbamate (intermediate 108,2.19 g, 6.16 mmol) and DMAP (753 mg, 6.16 mmol) in DMA (15 ml) washeated at 90° C. for 3.5 h. The cooled reaction mixture was partitionedbetween EtOAc and, the organic layer dried over MgSO₄ and evaporated.The residue was purified by reversed phase chromatography (RP 4) and theproduct containing fractions were partitioned between saturated aqueousNaHCO₃ and EtOAc, the organic layer dried over MgSO₄ and vaporated. Theresidue was then triturated with a mixture of DCM, Et₂O and heptane togive the title compound as a white solid. (UPLC-MS 7) t_(R) 0.80; ESI-MS554.4 [M+H]⁺.

Intermediate 108: phenyl(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)carbamate

Phenyl chloroformate (4.93 ml, 39.3 mmol) was added drop wise to amixture of 6-amino-4-(2-methoxyethoxy)nicotinonitrile (intermediate 20,3.45 g, 17.86 mmol) and pyridine (6.35 ml, 79 mmol) in THF (100 ml) atroom temperature. The reaction mixture was stirred for 5 h at roomtemperature and then partitioned between EtOAc and saturated aqueousNaHCO₃ solution, the organic layer washed with saturated brine, driedover MgSO₄ and evaporated. The residue was triturated with EtOAc and theproduct obtained by filtration as a white solid. (UPLC-MS 7) t_(R) 0.97;ESI-MS 314.3 [M+H]⁺.

Example 205:(R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

From intermediates 145 and 81, coupled in an analogous manner tointermediate 236, but using DMF instead of THF, and deprotected in ananalogous manner to Example 201. The title compound was obtained as anoff-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.84 (s, 1H), 10.12 (s, 1H), 8.61 (s, 1H),8.00 (s, 1H), 7.57 (s, 1H), 4.91 (s, 2H), 4.87 (m, 1H), 4.00 (m, 2H),3.59 (m, 2H), 3.33 (s, 3H), 3.29 (m, 2H), 3.07 (s, 2H), 2.95 (m, 2H),2.63 (m, 2H), 2.25 (s, 3H), 1.95 (m, 2H), 1.34 (d, 3H).

(UPLC-MS 6) t_(R) 0.82 min, ESI-MS 522.2 [M+H]⁺.

The following salts were prepared from the above free base form of(R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamideby precipitation with the appropriate counterions.

Tartrate with 1:1 stoichiometry (mw 671.66): A solution ofL-(+)-tartaric acid in acetone (0.1 M, 2.0 ml, 0.200 mmol) was added toa suspension of(R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(103 mg, 0.197 mmol) in acetone (4 ml) at room temperature. The mixturewas warmed to 55° C., maintained at this temperature for 2.5 h withsonication and then cooled slowly to 5° C. The precipitate that formedwas collected by filtration and dried under vacuum at 40° C. to give thetitle compound.

¹H NMR (600 MHz, DMSO-d₆) δ 13.83 (s, 1H), 10.11 (s, 1H), 8.60 (s, 1H),7.99 (s, 1H), 7.57 (s, 1H), 4.91 (s, 2H), 4.87 (m, 1H), 4.46 (s, 2H),4.00 (m, 2H), 3.59 (m, 2H), 3.33 (s, 3H), 3.29 (m, 2H), 3.09 (s, 2H),2.95 (m, 2H), 2.66 (m, 2H), 2.26 (s, 3H), 1.95 (m, 2H), 1.34 (d, 3H).

Tosylate with 1:1 stoichiometry (mw 693.78): A solution of tosic acid inacetone (0.1 M, 2.0 ml, 0.200 mmol) was added to a suspension of(R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(100 mg, 0.192 mmol) in acetone (4 ml) at room temperature. The mixturewas warmed to 55° C., maintained at this temperature for 2.5 h withsonication and then cooled slowly to room temperature. After standing 18h at 5° C. n-hexane (6 ml) was added, the solid collected by filtrationand then dried under vacuum to give the title compound.

¹H NMR (600 MHz, DMSO-d₆) δ 13.80 (s, 1H), 10.09 (s, 1H), 8.59 (s, 1H),7.98 (s, 1H), 7.68 (s, 1H), 7.41 (d, 2H), 7.07 (d, 2H), 4.96 (s, 2H),4.86 (m, 1H), 4.00 (m, 2H), 3.58 (m, 2H), 3.53 (m, 2H), 3.36 (br, m,5H), 3.32 (s, 3H), 2.94 (s, 2H), 2.90 (m, 2H), 2.28 (s, 3H), 1.95 (m,2H), 1.34 (d, 3H).

Citrate with 1:1 stoichiometry (mw 713.71): A solution of citric acid inacetone (0.1 M, 2.0 ml, 0.200 mmol) was added to a suspension of(R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(100 mg, 0.192 mmol) in acetone (4 ml) at room temperature. The mixturewas warmed to 55° C., maintained at this temperature for 2.5 h withsonication and then cooled slowly to room temperature. After standing 18h at 5° C. the solid was collected by filtration, washed with acetoneand then dried under vacuum to give the title compound.

¹H NMR (600 MHz, DMSO-d₆) δ 13.81 (s, 1H), 10.10 (s, 1H), 8.59 (s, 1H),7.98 (s, 1H), 7.56 (s, 1H), 4.90 (s, 2H), 4.85 (m, 1H), 3.98 (m, 2H),3.58 (m, 2H), 3.32 (s, 3H), 3.30 (m, 2H), 3.13 (s, 2H), 2.94 (m, 2H),2.73 (d, 2H), 2.70 (m, 2H), 2.64 (d, 2H), 2.29 (s, 3H), 1.95 (m, 2H),1.34 (d, 3H).

Malate with 1:1 stoichiometry (mw 655.58): A solution of L-malic acid inacetone (0.1 M, 2.0 ml, 0.200 mmol) was added to a suspension of(R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide(100 mg, 0.192 mmol) in acetone (4 ml) at room temperature. The mixturewas warmed to 55° C., maintained at this temperature for 2.25 h withsonication and then cooled to room temperature. n-Hexane (6 ml) wasadded, the solid was collected by filtration and then dried under vacuumto give the title compound.

¹H NMR (600 MHz, DMSO-d₆) δ 13.84 (s, 1H), 10.11 (s, 1H), 8.60 (s, 1H),7.99 (s, 1H), 7.56 (s, 1H), 4.91 (s, 2H), 4.87 (m, 1H), 4.22 (m, 1H),3.99 (m, 2H), 3.59 (m, 2H), 3.33 (s, 3H), 3.29 (m, 2H), 3.09 (s, 2H),2.95 (m, 2H), 2.66 (m, 2H), 2.61 (m, 1H), 2.44 (m, 1H), 2.26 (s, 3H),1.95 (m, 2H), 1.34 (d, 3H).

Intermediate 145: (R)-phenyl(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)carbamate

Phenyl chloroformate (1.53 ml, 12.2 mmol) was added drop wise to amixture of (R)-6-amino-4-((1-methoxypropan-2-yl)oxy)nicotinonitrile(intermediate 146, 1.37 g, 5.55 mmol) and pyridine (0.99 ml, 12.2 mmol)in THF (60 ml) at 0° C. The reaction mixture was stirred for 12 h atroom temperature and additional pyridine (0.98 ml, 12.2 mmol) and phenylchloroformate (1.53 ml, 12.2 mmol) were added. After stirring for afurther 36 h at room temperature the reaction mixture was partitionedbetween EtOAc and saturated aqueous NaHCO₃ solution, the organic layerwashed with saturated brine, dried over MgSO₄ and evaporated. Theresidue was triturated with Et₂O and the product obtained by filtrationas a white solid. (UPLC-MS 6) t_(R) 1.04; ESI-MS 328.4 [M+H]⁺.

Intermediate 146:(R)-6-amino-4-((1-methoxypropan-2-yl)oxy)nicotinonitrile

A solution of KHMDS in THF (1M, 43.8 ml, 43.8 mmol) was added to asolution of (R)-1-methoxypropanol (4.3 ml, 43.8 mmol) in THF (50 ml) atroom temperature under a positive argon pressure. After stirring for 15minutes at room temperature a solution of6-amino-4-fluoronicotinonitrile (intermediate 21, 3.0 g, 21.88 mmol) inTHF (30 ml) was added drop wise. The reaction mixture was stirred for 65h at room temperature, partitioned between aqueous NH₄Cl and EtOAc,extracted 2× with EtOAc, dried over Na₂SO₄ and evaporated. The residuewas triturated with Et₂O to give the title compound as a beige solid. ¹HNMR (400 MHz, DMSO-d₆) δ 8.14 (s, 1H), 6.82 (s, br, 2H), 6.09 (s, 1H),4.64-4.56 (m, 1H), 3.19 (s, 3H), 3.48 (d, 2H), 1.24 (d, 3H).

Reference Intermediate 236:N-(5-cyanopyridin-2-yl)-2-(dimethoxymethyl)-7,8-dihydro-5H-pyrido[2,3-b]azepine-9(6H)-carboxamide

A mixture of2-(dimethoxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine(intermediate 237, 35 mg, 0.154 mmol), phenyl(5-cyanopyridin-2-yl)carbamate (intermediate 240, 122 mg, 0.509 mmol)and DMAP (28.3 mg, 0.231 mmol) in THF (1.7 ml) was heated at reflux for23 h. The reaction mixture was diluted with sat. aq. NaHCO₃ andextracted with DCM (3×). The combined organic layers were dried overNa₂SO₄ and evaporated. The crude material was applied to a 40 g RediSep®silica column and purified by normal phase chromatography, eluting with99:1 DCM/MeOH. Product-containing fractions were combined andevaporated. The residue was triturated with Et₂O and the solid removedby filtration. The filtrate was concentrated and the residue trituratedwith MeOH to give the title compound as a white solid. (UPLC-MS 6) t_(R)1.06; ESI-MS 368.1 [M+H]⁺.

Reference Intermediate 237:2-(dimethoxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine

A microwave vial was charged with a mixture of tert-butyl2-formyl-7,8-dihydro-5H-pyrido[2,3-b]azepine-9(6H)-carboxylate(intermediate 238, 415 mg, 1.277 mmol) and p-toluenesulfonic acidmonohydrate (110 mg, 0.573 mmol) in MeOH (64 ml), sealed and then heatedat 135° C. for 3.5 h. The reaction mixture was concentrated and theresidue partitioned between sat. aq. NaHCO₃ and EtOAc. The aq. phase wasextracted with EtOAc (2×)—the combined organic layers were dried overNa₂SO₄ and evaporated. The crude material was applied to a 120 gRediSep® silica column and purified by normal phase chromatography,eluting with EtOAc. Product-containing fractions were combined andevaporated to give the title compound as a light yellow oil. (UPLC-MS 6)t_(R)0.60; ESI-MS 223.1 [M+H]⁺.

Reference Intermediate 238: tert-butyl2-formyl-7,8-dihydro-5H-pyrido[2,3-b]azepine-9(6H)-carboxylate

Ozone was bubbled through a mixture of tert-butyl2-vinyl-7,8-dihydro-5H-pyrido[2,3-b]azepine-9(6H)-carboxylate(intermediate 239, 470 mg, 1.66 mmol) in DCM (6.5 ml) at −78° C. After15 minutes, the intermediate ozonide was treated with dimethyl sulfide(0.86 ml, 11.62 mmol) and then the reaction mixture was slowly warmed toroom temperature. After 1.5 h, the mixture was diluted with H₂O andextracted with DCM (3×). The combined organic layers were washed withsat. aq. NaHCO₃ and brine, dried over Na₂SO₄ and evaporated to give thecrude title compound as a light brown solid. (UPLC-MS 6) t_(R) 1.04;ESI-MS 277.1 [M+H]⁺.

Reference Intermediate 239: tert-butyl2-vinyl-7,8-dihydro-5H-pyrido[2,3-b]azepine-9(6H)-carboxylate

A degassed mixture of tert-butyl2-chloro-7,8-dihydro-5H-pyrido[2,3-b]azepine-9(6H)-carboxylate (690 mg,2.44 mmol), potassium trifluoro(vinyl)borate (344 mg, 2.44 mmol),PdCl₂(dppf).CH₂Cl₂ (199 mg, 0.244 mmol) and Cs₂CO₃ (2.00 g, 6.1 mmol) inTHF (50 ml) and H₂O (10 ml) was heated at 80° C. for 3.5 h. The reactionmixture was diluted with H₂O and extracted with DCM (2×). The combinedorganic layers were dried over Na₂SO₄ and evaporated. The crude materialwas applied to a 120 g RediSep® silica column and purified by normalphase chromatography, eluting with 1:3 EtOAc/heptanes.Product-containing fractions were combined and evaporated to give thetitle compound as an off-white solid. (UPLC-MS 6) t_(R) 1.18; ESI-MS275.2 [M+H]⁺.

Reference Intermediate 240: phenyl (5-cyanopyridin-2-yl)carbamate

From 2-amino-5-cyanopyridine, reacted in an analogous manner to thepreparation of intermediate 108. (UPLC-MS 6) t_(R) 0.92; ESI-MS 240.1[M+H]⁺.

Reference Example 201:N-(5-cyanopyridin-2-yl)-2-formyl-7,8-dihydro-5H-pyrido[2,3-b]azepine-9(6H)-carboxamide

Concentrated hydrochloric acid (0.65 ml) was added to a solution ofN-(5-cyanopyridin-2-yl)-2-(dimethoxymethyl)-7,8-dihydro-5H-pyrido[2,3-b]azepine-9(6H)-carboxamide(reference intermediate 236, 29 mg, 0.079 mmol) in THF (0.9 ml) at roomtemperature. After stirring for 1 h at room temperature sat. aq. NaHCO₃was added and the mixture extracted with DCM (3×). The combined organiclayers were washed with brine, dried over Na₂SO₄ and evaporated. Theresidue was triturated with Et₂O to give the title compound as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (br s, 1H), 9.88 (s, 1H), 8.67 (m,1H), 8.20 (m, 1H), 8.11 (d, 1H), 8.04 (d, 1H), 7.84 (s, 1H), 3.73 (m,2H), 2.91 (m, 2H), 1.82 (m, 2H), 1.72 (m, 2H). (UPLC-MS 6) t_(R) 0.93min, ESI-MS 322.1 [M+H]⁺.

Cell Proliferation Assay

Methylene Blue Staining Proliferation Assay (MBS):

The effect of compounds on cell proliferation is assessed using HuH-7hepatocellular carcinoma cells obtained from the Japanese Collection ofResearch Bioresources Cell Bank (Cat# JCRB0403) and cultured in thevendor-recommended medium (DMEM high glucose (Amimed Cat#1-26F01-1), 10%foetal calf serum (Invitrogen Cat#16140-071), 1 mM sodium pyruvate(Amimed Cat#5-60F00-H), 1× Penicillin/Streptomycin (AmimedCat#4-01F00-H)) at 37° C. in a humidified 5% CO2 incubator.Specifically, 5000 cells/well were seeded in 96-well tissue cultureplates (TPP Cat#92696) in a total media volume of 100 μl/well andincreasing compound dilutions or DMSO were added 24 hours thereafter intriplicates. 72 hours after compound addition, cells were fixed byadding 25 μL/well of 20% glutaraldehyde (Sigma Aldrich Cat# G400-4) andincubated for 10 minutes at room temperature. Cells were washed threetimes with H₂O, 200 μL/well and stained with 100 μL/well 0.05% methyleneblue (ABCR GmbH Cat# AB117904) for 10 minutes at room temperature. Cellswere washed 3 times with H2O, 200 μL/well and then lysed by adding 200μL/well of 3% HCl (Fluka Cat#84422) for 30 minutes at room temperaturewith shaking. Optical density was measured at A650 nm. The concentrationof compound providing 50% of proliferation inhibition with respect toDMSO-treated cells was determined (IC₅₀) using XLFit software.

The effect of compounds on cell proliferation using Hep 3B2.1-7hepatocellular carcinoma cells, FU97 gastric cancer cells, JHH7hepatocellular carcinoma cells or JHH6 hepatocellular carcinoma cells isassessed as above. Hep 3B2.1-7, FU97, JHH7 or JHH6 are obtained from theJapanese Collection of Research Bioresources Cell Bank. Hep 3B2.1-7cells are cultured in EMEM+10% FCS+1 mM Na pyruvate+2 mM L-glutamine and2000 cells/well are seeded for the proliferation assay. FU97 cells arecultured in DMEM high glucose+10% FCS+1 mM Na pyruvate+4 mML-glutamine+1×ITS and 2000 cells/well are seeded for the proliferationassay. JHH6 and JHH7 cells are cultured in William's E+10% FCS+2 mML-glutamine and 3000 cells are seeded for the proliferation assay.

CellTiter Glo (CTG) Assay:

The functional effect of compounds on cell proliferation is assessedusing HuH-7 hepatocellular carcinoma cells obtained from the JapaneseCollection of Research Bioresources Cell Bank (Cat# JCRB0403) andcultured in the vendor-recommended medium (DMEM high glucose (AmimedCat#1-26F01-I), 10% foetal calf serum (Invitrogen Cat#16140-071), 1 mMsodium pyruvate (Amimed Cat#5-60F00-H), 1× Penicillin/Streptomycin(Amimed Cat#4-01F00-H)) at 37° C. in a humidified 5% CO2 incubator.Compound-mediated suppression of cell proliferation/viability isassessed by quantification of cellular ATP levels using theCellTiter-Glo (CTG) reagent (Promega, Cat# G7573). Briefly, cells areseeded at 3′000 cells/well/80 μl fresh medium intotissue-culture-treated 96-well plates (Costar Cat#3904), followed byaddition of 20 μl medium containing compound dilutions at 5-fold theirfinal intended concentration. Dose-response effects are assessed by3-fold serial dilutions of the test compound, starting at 10 μM.Following incubation of the cells for 3 days at 37° C. and 5% CO02, theeffect of inhibitors on cell viability is quantified following additionof 50 μl CTG and luminescence measurement (integration time: 500 ms) asper vendor manual, using a correspondingly equipped multi-mode platereader (M200Pro, TECAN, Switzerland). For data analysis, the assaybackground value determined in wells containing medium, but no cells, issubtracted from all data points. To enable differentiation of cytotoxicfrom cytostatic compounds, the number of viable cells is assessedrelative to that observed at the time of compound addition using aseparate cell plate (day 0). The effect of a particular test compoundconcentration on cell proliferation/viability is expressed as percentageof the background- and day 0-corrected luminescence reading obtained forcells treated with vehicle only (DMSO, 0.1% f.c.), which is set as 100%,whereas the luminescence reading for wells containing medium only, butno cells, is set as −100%. Compound concentrations leading tohalf-maximal growth inhibition (GI50) are determined using standard fourparameter curve fitting (XLfit 5.2., IDBS, UK).

Hep3B JHH7 FU97 prolif- prolif- prolif- HUH7 proliferation erationeration eration (nM) (nM) (nM) (nM) Example MBS CTG MBS MBS MBS3 >3000 >3000 nd nd nd 27 >3000 n.d. 719 >3,000 nd 39 123569 >3,000 >3,000 nd 49 n.d. 463 nd nd nd 50 270.3 436 453 484 234  63106 n.d. >3,000 >3,000 nd 68 1092 n.d. >3,000 >3,000 nd 80 72 168 73 15096 83 12 60.9 1 9 23 92 n.d. 38 nd nd nd 101 82 142 21 nd nd 205 14.017.8 5 nd nd

In order to confirm their efficacy, the compounds can be tested in thefollowing in vivo assay.

In Vivo Assay

Subcutaneous tumors in nude mice were induced by injecting a total of5×10⁶ cells in 100 μl HBSS containing 50% Matrigel in the flank of nudemice. Treatment with compounds starts approximately 3 weeks post cellinjection with an average tumor size of around 150-200 mm³. Animals arerandomized into groups of n=6 for vehicle control and each tested doseof the compound. Animals were treated for at least 14 days to assessanti-tumor effect and tolerability. Measurement of tumor size wasperformed with a caliper 2 times per week. Tumor volume (TVol) wascalculated in mm3 using the formula (Length x Width)× π/6. Tumorresponse was quantified by calculating the change in tumor volume(endpoint minus starting value) as the T/C, i.e.(ΔTVoldrug/ΔTVolvehicle×100). In the case of tumor regression, the tumorresponse was quantified by the percentage of regression of the startingtumor volume, i.e. (ΔTVoldrug/ΔTVolday0×100). Statistical analysis wasperformed by comparing the treatment groups to the vehicle control groupat endpoint using Kruskal-Wallis followed by Dunn's post hoc test. Atleast one compound of the invention showed 70% tumour regression.

Assay for Biomarkers (FGFR4, FGF19 and KLB)

FGF19 protein levels are measured using the human FGF-19 DuoSet DY969from R&D Systems following the indications of the manufacturer.

Briefly, the capture antibody was diluted in PBS to a working dilutionof 4 μg/mL and used to coat a 96-well plate (Costar #2592) with 100μl/well at room temperature overnight. Plates were washed 6 times with400 μl/well of PBS/0.05% Tween20 and blocked by adding 300 μl/well ofassay diluent (1% BSA in PBS) for 2 hours at room temperature. Plateswere washed 6 times with 400 μl/well of PBS/0.05% Tween20.

Cell lines were lysed using MPER lysis buffer (Pierce #78501)supplemented with Complete protease inhibitor tablets (Roche#11836145001) and PhosStop phosphatase inhibitor tablets (Roche#04906837001) on ice for 30 minutes. Lysates were clarified bycentrifugation at 12000×g for 15 minutes and protein concentration wasdetermined using the DC protein assay reagents (Bio Rad #500-0116) and aBSA standard. Cell lysates were diluted in PBS/1% BSA to add 100 μg/welland 10 μg/well in 100 μL. A 7-points standard ranging from 1000 μg/mL to15.625 μg/mL was prepared. Samples and standards were added onto thecoated plate, covered with a plate sealer and incubated for 2 hours on aplate mixer followed by 4 washings with 400 μl/well of PBS/0.05%Tween20.

The detection antibody, diluted to a working concentration of 100 ng/mLin PBS/1% BSA, was added in 100 μl/well and incubated at roomtemperature for 2 hours on a plate mixer followed by 4 washings with 400μl/well of PBS/0.05% Tween20.

The streptavidin solution diluted in PBS/1% BSA was added onto the plateand incubated at room temperature, protected from light for 20 minutesfollowed by 3 washing with 400 μl/well of PBS/0.05% Tween20.

100 μl/well of substrate solution were added and incubated at roomtemperature, protected from light for 20 minutes followed by 50 μl/wellof Stop solution.

The optical density of the plate was determined using a microplatereader set at 450 nm.

FGFR4 protein levels are quantified by performing sandwich-type captureELISA on cell lysate. Cells were lysed as above.

96-well ELISA plates (NUNC #437111) were pre-coated with mouseanti-FGFR4 mAb (R&D Systems #MAB685), 100 μl each diluted 1:100 in PBSwithout Ca2+/Mg2+. Following incubation for 1 hour at room temperatureon an orbital shaker, 150 μl 3% MSD blocker A (MesoScale Discovery#R93BA-4) in TBS complemented with 0.05% Tween-20 (TBST-T) was added for1 hour at room temperature. The wells were washed with 3 changes of 200μl TBST-T.

Equal aliquots of the protein lysates were added to two pre-coated96-well ELISA plates. Additional wells to assess the assay backgroundwere incubated with 100 μl lysis buffer/MSD Blocker A 1% (3:1) buffermix. After an overnight incubation at 4° C., wells were washed with 3changes of 200 μl TBS-T. ELISA-plates pre-coated with the captureantibody were then incubated for 1.5 hours with 100 μl rabbit anti-FGFR4mAb (Cell Signaling Technology #8562) diluted 1:1000 in 1% MSD blockingbuffer at room temperature on an orbital shaker. Following 3 washes with200 μl TBS-T, wells were incubated for 1.5 hours with 100 μl of alkalinephosphatase conjugated F(ab′)2 fragment of goat anti-rabbit IgG(Invitrogen #F-21456) diluted 1:20,000 in 1% MSD blocking buffer at roomtemperature on an orbital shaker. After washing with 3 changes of 200 μlTBS-T and a final wash with 200 μl distilled water, wells were incubatedwith 90 μl of Tropix CDP-Star Ready to use with Emerald II (AppliedBiosystems #T2216) for 40 minutes in the dark. Luminescence was recordedon an InfiniteM1000 plate reader (TECAN). Values obtained in the wellscontaining lysis/BSA-buffer only were averaged and subtracted from thewells containing lysate samples.

KLB protein levels are quantified by western blot. Cells were lysed asabove. 50 μg of cell lysates were loaded onto 4-12% gradient NuPAGEBis-Tris gels (Invitrogen #WG1402BX10) and blotted onto PVDF membranes.Filters were blocked in 5% milk for 1 hour at room temperature. Theprimary anti-human Klotho-β antibody (R&D Systems #AF5889) was used at 2μg/mL. Signal detection was done using a secondary anti-goat-HRPantibody (Sigma #A5420). 1-tubulin was used as an internal control, andthe detection was performed with anti-β-tubulin antibody (Sigma clone2.1) followed by a secondary anti-mouse-HRP antibody (Amersham NA931).Membranes were imaged using the Fusion FX7 imaging system, and KLBlevels were expressed as % of 3-tubulin levels. The detection was donewith super-signal west dura substrate (Thermo Signal, #34076).

FGF19 FGFR4 Cell line (pg/mL) (luminescence units) KLB (% of β-tubulin)HUH7 1080 1305930 3.36 Hep3B 399 700932 4.13 JHH7 4410 537741 1.12 Fu97841 1164087 6.39 JHH6 BLQ 853 BLQ BLQ indicates below limit of detectionusing the corresponding assay.

Negative Control

The compounds of the invention can be measured in a JHH6 cellproliferation assay (described above). A compound of the inventionmeasured in this assay showed an IC50>10000 nM.

1. A method of treating solid malignancies characterized by positiveFGFR4 and FGF19 expression or by positive FGFR4 and KLB expression witha compound of formula (I) or a pharmaceutically acceptable salt thereof

wherein V is selected from CH₂, O, CH(OH); W is selected from CH₂,CH₂CH₂, bond; X is C(R^(X)) or N; Y is C(R^(Y)) or N; Z is CH or N;wherein when X is N, Y and Z are not N; wherein when Y is N, X and Z arenot N; wherein when Z is N, X and Y are not N; R^(X) is selected fromhydrogen, halogen, haloC₁-C₃alkyl, cyano, C₁-C₆alkyl, hydroxyC₁-C₆alkyl;R^(Y) is selected from hydrogen, halogen, C₁-C₃alkyl, C₁-C₆alkoxy,hydroxyC₁-C₃alkoxy, NR^(Y1)R^(Y2), cyano, C₁-C₃alkoxyC₁-C₃alkoxy,C₁-C₃alkoxy-haloC₁-C₃alkoxy, di(C₁-C₃alkyl)aminoC₁-C₆alkoxy,O—(CH₂)₀₋₁—R^(Y3), CR^(Y6)R^(Y7), S—C₁-C₃alkyl, haloC₁-C₆alkoxyoptionally substituted with hydroxy; or R^(X) and R^(Y) together withthe ring to which they are attached form a bicyclic aromatic ring systemoptionally further comprising one or two heteroatoms selected from N, O,or S, which ring system is optionally substituted with C₁-C₃alkyl;R^(Y1) is hydrogen and R^(Y2) is C₁-C₆alkyl; hydroxyC₁-C₆alkyl;haloC₁-C₆alkyl optionally substituted with hydroxy;C₁-C₄alkoxyC₁-C₆alkyl; haloC₁-C₃alkoxyC₁-C₆alkyl; (CH₂)₀₋₁—R^(Y4);di(C₁-C₃alkyl)aminoC₁-C₆alkyl substituted with hydroxy;bicyclo[2.2.1]heptanyl substituted with hydroxyC₁-C₃alkyl; phenylsubstituted with S(O)₂—CH(CH₃)₂; bicycloC₅-C₈alkyl; C₂-C₃alkylsulfonicacid; or R^(Y1) and R^(Y2) together with the N atom to which they areattached form a saturated or unsaturated non-aromatic 6-memberedheterocyclic ring which may contain an O atom, which ring may besubstituted once or twice by R^(Y5); R^(Y3) is selected fromquinuclidinyl, a 4-, 5- or 6-membered saturated heterocyclic ringcomprising at least one heteroatom selected from N, O or S, or a 5- or6-membered aromatic heterocyclic ring, which saturated or aromaticheterocyclic ring is optionally substituted with C₁-C₃alkyl and/or oxo;R^(Y4) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O, or S, which ring isoptionally substituted with C₁-C₃alkyl; R^(Y5) is independently selectedfrom C₁-C₃alkyl, hydroxy, di(C₁-C₃alkyl)aminoC₁-C₃alkyl, or two R^(Y5)attached at the same carbon atom form together with the carbon atom towhich they are attached a 5-membered saturated heterocyclic ringcomprising at least one heteroatom selected from N, O or S, which ringis substituted once or more than once with C₁-C₃alkyl; R^(Y6) and R^(Y7)together with the carbon atom to which they are attached form a6-membered saturated or unsaturated non-aromatic heterocyclic ringcomprising one heteroatom selected from N, O or S; R¹ is selected fromhydrogen; halogen; C₁-C₃alkyl; haloC₁-C₃alkyl; hydroxyC₁-C₃alkyl;C₃-C₆cycloalkyl; CH₂NR²R³; CH(CH₃)NR²R³; C₁-C₃alkoxyC₁-C₃alkyl; CH₂CO₂H;C(O)H; C₁-C₃alkoxy; a 5- or 6-membered saturated heterocyclic oraromatic heterocyclic ring comprising at least one heteroatom selectedfrom N, O or S, which ring is optionally substituted once or more thanonce with a group independently selected from C₁-C₃alkyl,haloC₁-C₃alkyl, oxetanyl or oxo; R² is selected from C₁-C₃alkyl,di(C₁-C₃alkyl)aminoC₁-C₃alkyl; R³ is selected from C₁-C₃alkyl,C(O)C₁-C₃alkyl, C(O)—CH₂—OH, C(O)—CH₂—O—CH₃, C(O)—CH₂—N(CH₃)₂, S(O)₂CH₃;or R² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, N-oxide, O or S, which ring may besubstituted once or more than once with R⁴; R⁴ is independently selectedfrom C₁-C₃alkyl, di(C₁-C₃alkyl)amino, C(O)CH₃, hydroxy; or two R⁴attached at the same carbon atom form together with the carbon atom towhich they are attached a 4-, 5- or 6-membered non-aromatic heterocyclicring comprising at least one heteroatom selected from N, O or S; or twoR⁴ attached at the same ring atom form an oxo group; and R⁵ is selectedfrom hydrogen or C₁-C₃alkyl.
 2. A method according to claim 1, whereinthe solid malignancies are characterized by positive FGFR4, FGF19 andKLB expression.
 3. A method according to claim 1, wherein the solidmalignancies are from a cancer selected from liver cancer, breastcancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer,ovarian cancer, lung cancer, colon cancer.
 4. A method of treating apatient having solid malignancies, characterized in that the compound offormula (I) or a pharmaceutically acceptable salt thereof is to beadministered to the patient on the basis of said patient having positiveFGFR4 and KLB expression, or positive FGFR4 and FGF19 expression, orpositive FGFR4, KLB and FGF19 expression with a compound of formula (I)or a pharmaceutically acceptable salt thereof

wherein V is selected from CH₂, O, CH(OH); W is selected from CH₂,CH₂CH₂, bond; X is C(R^(X)) or N; Y is C(R^(Y)) or N; Z is CH or N;wherein when X is N, Y and Z are not N; wherein when Y is N, X and Z arenot N; wherein when Z is N, X and Y are not N; R^(X) is selected fromhydrogen, halogen, haloC₁-C₃alkyl, cyano, C₁-C₆alkyl, hydroxyC₁-C₆alkyl;R^(Y) is selected from hydrogen, halogen, C₁-C₃alkyl, C₁-C₆alkoxy,hydroxyC₁-C₃alkoxy, NR^(Y1)R^(Y2), cyano, C₁-C₃alkoxyC₁-C₃alkoxy,C₁-C₃alkoxy-haloC₁-C₃alkoxy, di(C₁-C₃alkyl)aminoC₁-C₆alkoxy,O—(CH₂)₀₋₁—R^(Y3), CR^(Y6)R^(Y7), S—C₁-C₃alkyl, haloC₁-C₆alkoxyoptionally substituted with hydroxy; or R^(X) and R^(Y) together withthe ring to which they are attached form a bicyclic aromatic ring systemoptionally further comprising one or two heteroatoms selected from N, O,or S, which ring system is optionally substituted with C₁-C₃alkyl;R^(Y1) is hydrogen and R^(Y2) is C₁-C₆alkyl; hydroxyC₁-C₆alkyl;haloC₁-C₆alkyl optionally substituted with hydroxy;C₁-C₄alkoxyC₁-C₆alkyl; haloC₁-C₃alkoxyC₁-C₆alkyl; (CH₂)₀₋₁—R^(Y4);di(C₁-C₃alkyl)aminoC₁-C₆alkyl substituted with hydroxy;bicyclo[2.2.1]heptanyl substituted with hydroxyC₁-C₃alkyl; phenylsubstituted with S(O)₂—CH(CH₃)₂; bicycloC₅-C₈alkyl; C₂-C₃alkylsulfonicacid; or R^(Y1) and R^(Y2) together with the N atom to which they areattached form a saturated or unsaturated non-aromatic 6-memberedheterocyclic ring which may contain an O atom, which ring may besubstituted once or twice by R^(Y5); R^(Y3) is selected fromquinuclidinyl, a 4-, 5- or 6-membered saturated heterocyclic ringcomprising at least one heteroatom selected from N, O or S, or a 5- or6-membered aromatic heterocyclic ring, which saturated or aromaticheterocyclic ring is optionally substituted with C₁-C₃alkyl and/or oxo;R^(Y4) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O, or S, which ring isoptionally substituted with C₁-C₃alkyl; R^(Y5) is independently selectedfrom C₁-C₃alkyl, hydroxy, di(C₁-C₃alkyl)aminoC₁-C₃alkyl, or two R^(Y5)attached at the same carbon atom form together with the carbon atom towhich they are attached a 5-membered saturated heterocyclic ringcomprising at least one heteroatom selected from N, O or S, which ringis substituted once or more than once with C₁-C₃alkyl; R^(Y6) and R^(Y7)together with the carbon atom to which they are attached form a6-membered saturated or unsaturated non-aromatic heterocyclic ringcomprising one heteroatom selected from N, O or S; R¹ is selected fromhydrogen; halogen; C₁-C₃alkyl; haloC₁-C₃alkyl; hydroxyC₁-C₃alkyl;C₃-C₆cycloalkyl; CH₂NR²R³; CH(CH₃)NR²R³; C₁-C₃alkoxyC₁-C₃alkyl; CH₂CO₂H;C(O)H; C₁-C₃alkoxy; a 5- or 6-membered saturated heterocyclic oraromatic heterocyclic ring comprising at least one heteroatom selectedfrom N, O or S, which ring is optionally substituted once or more thanonce with a group independently selected from C₁-C₃alkyl,haloC₁-C₃alkyl, oxetanyl or oxo; R² is selected from C₁-C₃alkyl,di(C₁-C₃alkyl)aminoC₁-C₃alkyl; R³ is selected from C₁-C₃alkyl,C(O)C₁-C₃alkyl, C(O)—CH₂—OH, C(O)—CH₂—O—CH₃, C(O)—CH₂—N(CH₃)₂, S(O)₂CH₃;or R² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, N-oxide, O or S, which ring may besubstituted once or more than once with R⁴; R⁴ is independently selectedfrom C₁-C₃alkyl, di(C₁-C₃alkyl)amino, C(O)CH₃, hydroxy; or two R⁴attached at the same carbon atom form together with the carbon atom towhich they are attached a 4-, 5- or 6-membered non-aromatic heterocyclicring comprising at least one heteroatom selected from N, O or S; or twoR⁴ attached at the same ring atom form an oxo group; and R⁵ is selectedfrom hydrogen or C₁-C₃alkyl.
 5. A method of treating a patient havingsolid malignancies, characterized in that The patient is selected fortreatment on the basis of the patient having positive FGFR4 and KLBexpression, or positive FGFR4 and FGF19 expression, or positive FGFR4,KLB and FGF19 expression; and then treated with a compound of formula(I) or a pharmaceutically acceptable salt thereof

wherein V is selected from CH₂, O, CH(OH); W is selected from CH₂,CH₂CH₂, bond; X is C(R^(X)) or N; Y is C(R^(Y)) or N; Z is CH or N;wherein when X is N, Y and Z are not N; wherein when Y is N, X and Z arenot N; wherein when Z is N, X and Y are not N; R^(X) is selected fromhydrogen, halogen, haloC₁-C₃alkyl, cyano, C₁-C₆alkyl, hydroxyC₁-C₆alkyl;R^(Y) is selected from hydrogen, halogen, C₁-C₃alkyl, C₁-C₆alkoxy,hydroxyC₁-C₃alkoxy, NR^(Y1)R^(Y2), cyano, C₁-C₃alkoxyC₁-C₃alkoxy,C₁-C₃alkoxy-haloC₁-C₃alkoxy, di(C₁-C₃alkyl)aminoC₁-C₆alkoxy,O—(CH₂)₀₋₁—R^(Y3), CR^(Y6)R^(Y7), S—C₁-C₃alkyl, haloC₁-C₆alkoxyoptionally substituted with hydroxy; or R^(X) and R^(Y) together withthe ring to which they are attached form a bicyclic aromatic ring systemoptionally further comprising one or two heteroatoms selected from N, O,or S, which ring system is optionally substituted with C₁-C₃alkyl;R^(Y1) is hydrogen and R^(Y2) is C₁-C₆alkyl; hydroxyC₁-C₆alkyl;haloC₁-C₆alkyl optionally substituted with hydroxy;C₁-C₄alkoxyC₁-C₆alkyl; haloC₁-C₃alkoxyC₁-C₆alkyl; (CH₂)₀₋₁—R^(Y4);di(C₁-C₃alkyl)aminoC₁-C₆alkyl substituted with hydroxy;bicyclo[2.2.1]heptanyl substituted with hydroxyC₁-C₃alkyl; phenylsubstituted with S(O)₂—CH(CH₃)₂; bicycloC₅-C₈alkyl; C₂-C₃alkylsulfonicacid; or R^(Y1) and R^(Y2) together with the N atom to which they areattached form a saturated or unsaturated non-aromatic 6-memberedheterocyclic ring which may contain an O atom, which ring may besubstituted once or twice by R^(Y5); R^(Y3) is selected fromquinuclidinyl, a 4-, 5- or 6-membered saturated heterocyclic ringcomprising at least one heteroatom selected from N, O or S, or a 5- or6-membered aromatic heterocyclic ring, which saturated or aromaticheterocyclic ring is optionally substituted with C₁-C₃alkyl and/or oxo;R^(Y4) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O, or S, which ring isoptionally substituted with C₁-C₃alkyl; R^(Y5) is independently selectedfrom C₁-C₃alkyl, hydroxy, di(C₁-C₃alkyl)aminoC₁-C₃alkyl, or two R^(Y5)attached at the same carbon atom form together with the carbon atom towhich they are attached a 5-membered saturated heterocyclic ringcomprising at least one heteroatom selected from N, O or S, which ringis substituted once or more than once with C₁-C₃alkyl; R^(Y6) and R^(Y7)together with the carbon atom to which they are attached form a6-membered saturated or unsaturated non-aromatic heterocyclic ringcomprising one heteroatom selected from N, O or S; R¹ is selected fromhydrogen; halogen; C₁-C₃alkyl; haloC₁-C₃alkyl; hydroxyC₁-C₃alkyl;C₃-C₆cycloalkyl; CH₂NR²R³; CH(CH₃)NR²R³; C₁-C₃alkoxyC₁-C₃alkyl; CH₂CO₂H;C(O)H; C₁-C₃alkoxy; a 5- or 6-membered saturated heterocyclic oraromatic heterocyclic ring comprising at least one heteroatom selectedfrom N, O or S, which ring is optionally substituted once or more thanonce with a group independently selected from C₁-C₃alkyl,haloC₁-C₃alkyl, oxetanyl or oxo; R² is selected from C₁-C₃alkyl,di(C₁-C₃alkyl)aminoC₁-C₃alkyl; R³ is selected from C₁-C₃alkyl,C(O)C₁-C₃alkyl, C(O)—CH₂—OH, C(O)—CH₂—O—CH₃, C(O)—CH₂—N(CH₃)₂, S(O)₂CH₃;or R² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, N-oxide, O or S, which ring may besubstituted once or more than once with R⁴; R⁴ is independently selectedfrom C₁-C₃alkyl, di(C₁-C₃alkyl)amino, C(O)CH₃, hydroxy; or two R⁴attached at the same carbon atom form together with the carbon atom towhich they are attached a 4-, 5- or 6-membered non-aromatic heterocyclicring comprising at least one heteroatom selected from N, O or S; or twoR⁴ attached at the same ring atom form an oxo group; and R⁵ is selectedfrom hydrogen or C₁-C₃alkyl.
 6. A method of treating a patient havingsolid malignancies, characterized in that a biological sample from thepatient is assayed for positive FGFR4 and KLB expression, or positiveFGFR4 and FGF19 expression, or positive FGFR4, KLB and FGF19 expression;and a compound of formula (I) or a pharmaceutically acceptable saltthereof is administered to the patient on the basis of the biologicalsample from the patient having positive FGFR4 and KLB expression, orpositive FGFR4 and FGF19 expression, or positive FGFR4, KLB and FGF19expression with the treatment of a compound of formula (I) or apharmaceutically acceptable salt thereof

wherein V is selected from CH₂, O, CH(OH); W is selected from CH₂,CH₂CH₂, bond; X is C(R^(X)) or N; Y is C(R^(Y)) or N; Z is CH or N;wherein when X is N, Y and Z are not N; wherein when Y is N, X and Z arenot N; wherein when Z is N, X and Y are not N; R^(X) is selected fromhydrogen, halogen, haloC₁-C₃alkyl, cyano, C₁-C₆alkyl, hydroxyC₁-C₆alkyl;R^(Y) is selected from hydrogen, halogen, C₁-C₃alkyl, C₁-C₆alkoxy,hydroxyC₁-C₃alkoxy, NR^(Y1)R^(Y2), cyano, C₁-C₃alkoxyC₁-C₃alkoxy,C₁-C₃alkoxy-haloC₁-C₃alkoxy, di(C₁-C₃alkyl)aminoC₁-C₆alkoxy,O—(CH₂)₀₋₁—R^(Y3), CR^(Y6)R^(Y7), S—C₁-C₃alkyl, haloC₁-C₆alkoxyoptionally substituted with hydroxy; or R^(X) and R^(Y) together withthe ring to which they are attached form a bicyclic aromatic ring systemoptionally further comprising one or two heteroatoms selected from N, O,or S, which ring system is optionally substituted with C₁-C₃alkyl;R^(Y1) is hydrogen and R^(Y2) is C₁-C₆alkyl; hydroxyC₁-C₆alkyl;haloC₁-C₆alkyl optionally substituted with hydroxy;C₁-C₄alkoxyC₁-C₆alkyl; haloC₁-C₃alkoxyC₁-C₆alkyl; (CH₂)₀₋₁—R^(Y4);di(C₁-C₃alkyl)aminoC₁-C₆alkyl substituted with hydroxy;bicyclo[2.2.1]heptanyl substituted with hydroxyC₁-C₃alkyl; phenylsubstituted with S(O)₂—CH(CH₃)₂; bicycloC₅-C₈alkyl; C₂-C₃alkylsulfonicacid; or R^(Y1) and R^(Y2) together with the N atom to which they areattached form a saturated or unsaturated non-aromatic 6-memberedheterocyclic ring which may contain an O atom, which ring may besubstituted once or twice by R^(Y5); R^(Y3) is selected fromquinuclidinyl, a 4-, 5- or 6-membered saturated heterocyclic ringcomprising at least one heteroatom selected from N, O or S, or a 5- or6-membered aromatic heterocyclic ring, which saturated or aromaticheterocyclic ring is optionally substituted with C₁-C₃alkyl and/or oxo;R^(Y4) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O, or S, which ring isoptionally substituted with C₁-C₃alkyl; R^(Y5) is independently selectedfrom C₁-C₃alkyl, hydroxy, di(C₁-C₃alkyl)aminoC₁-C₃alkyl, or two R^(Y5)attached at the same carbon atom form together with the carbon atom towhich they are attached a 5-membered saturated heterocyclic ringcomprising at least one heteroatom selected from N, O or S, which ringis substituted once or more than once with C₁-C₃alkyl; R^(Y6) and R^(Y7)together with the carbon atom to which they are attached form a6-membered saturated or unsaturated non-aromatic heterocyclic ringcomprising one heteroatom selected from N, O or S; R¹ is selected fromhydrogen; halogen; C₁-C₃alkyl; haloC₁-C₃alkyl; hydroxyC₁-C₃alkyl;C₃-C₆cycloalkyl; CH₂NR²R³; CH(CH₃)NR²R³; C₁-C₃alkoxyC₁-C₃alkyl; CH₂CO₂H;C(O)H; C₁-C₃alkoxy; a 5- or 6-membered saturated heterocyclic oraromatic heterocyclic ring comprising at least one heteroatom selectedfrom N, O or S, which ring is optionally substituted once or more thanonce with a group independently selected from C₁-C₃alkyl,haloC₁-C₃alkyl, oxetanyl or oxo; R² is selected from C₁-C₃alkyl,di(C₁-C₃alkyl)aminoC₁-C₃alkyl; R³ is selected from C₁-C₃alkyl,C(O)C₁-C₃alkyl, C(O)—CH₂—OH, C(O)—CH₂—O—CH₃, C(O)—CH₂—N(CH₃)₂, S(O)₂CH₃;or R² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, N-oxide, O or S, which ring may besubstituted once or more than once with R⁴; R⁴ is independently selectedfrom C₁-C₃alkyl, di(C₁-C₃alkyl)amino, C(O)CH₃, hydroxy; or two R⁴attached at the same carbon atom form together with the carbon atom towhich they are attached a 4-, 5- or 6-membered non-aromatic heterocyclicring comprising at least one heteroatom selected from N, O or S; or twoR⁴ attached at the same ring atom form an oxo group; R⁵ is selected fromhydrogen or C₁-C₃alkyl.
 7. A method of treating a patient having solidmalignancies comprising Assaying a biological sample from the patient;Determining if the biological sample from the patient is characterizedby positive FGFR4 and KLB expression, or by positive FGFR4 and FGF19expression, or by positive FGFR4, KLB and FGF19 expression; and If thebiological sample is characterized by positive FGFR4 and KLB expression,or by positive FGFR4 and FGF19 expression, or by positive FGFR4, KLB andFGF19 expression, administering a compound of formula (I) or apharmaceutically acceptable salt thereof to the patient with a compoundof formula (I) or a pharmaceutically acceptable salt thereof

wherein V is selected from CH₂, O, CH(OH); W is selected from CH₂,CH₂CH₂, bond; X is C(R^(X)) or N; Y is C(R^(Y)) or N; Z is CH or N;wherein when X is N, Y and Z are not N; wherein when Y is N, X and Z arenot N; wherein when Z is N, X and Y are not N; R^(X) is selected fromhydrogen, halogen, haloC₁-C₃alkyl, cyano, C₁-C₆alkyl, hydroxyC₁-C₆alkyl;R^(Y) is selected from hydrogen, halogen, C₁-C₃alkyl, C₁-C₆alkoxy,hydroxyC₁-C₃alkoxy, NR^(Y1)R^(Y2), cyano, C₁-C₃alkoxyC₁-C₃alkoxy,C₁-C₃alkoxy-haloC₁-C₃alkoxy, di(C₁-C₃alkyl)aminoC₁-C₆alkoxy,O—(CH₂)₀₋₁—R^(Y3), CR^(Y6)R^(Y7), S—C₁-C₃alkyl, haloC₁-C₆alkoxyoptionally substituted with hydroxy; or R^(X) and R^(Y) together withthe ring to which they are attached form a bicyclic aromatic ring systemoptionally further comprising one or two heteroatoms selected from N, O,or S, which ring system is optionally substituted with C₁-C₃alkyl;R^(Y1) is hydrogen and R^(Y2) is C₁-C₆alkyl; hydroxyC₁-C₆alkyl;haloC₁-C₆alkyl optionally substituted with hydroxy;C₁-C₄alkoxyC₁-C₆alkyl; haloC₁-C₃alkoxyC₁-C₆alkyl; (CH₂)₀₋₁—R^(Y4);di(C₁-C₃alkyl)aminoC₁-C₆alkyl substituted with hydroxy;bicyclo[2.2.1]heptanyl substituted with hydroxyC₁-C₃alkyl; phenylsubstituted with S(O)₂—CH(CH₃)₂; bicycloC₅-C₈alkyl; C₂-C₃alkylsulfonicacid; or R^(Y1) and R^(Y2) together with the N atom to which they areattached form a saturated or unsaturated non-aromatic 6-memberedheterocyclic ring which may contain an O atom, which ring may besubstituted once or twice by R^(Y5); R^(Y3) is selected fromquinuclidinyl, a 4-, 5- or 6-membered saturated heterocyclic ringcomprising at least one heteroatom selected from N, O or S, or a 5- or6-membered aromatic heterocyclic ring, which saturated or aromaticheterocyclic ring is optionally substituted with C₁-C₃alkyl and/or oxo;R^(Y4) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O, or S, which ring isoptionally substituted with C₁-C₃alkyl; R^(Y5) is independently selectedfrom C₁-C₃alkyl, hydroxy, di(C₁-C₃alkyl)aminoC₁-C₃alkyl, or two R^(Y5)attached at the same carbon atom form together with the carbon atom towhich they are attached a 5-membered saturated heterocyclic ringcomprising at least one heteroatom selected from N, O or S, which ringis substituted once or more than once with C₁-C₃alkyl; R^(Y6) and R^(Y7)together with the carbon atom to which they are attached form a6-membered saturated or unsaturated non-aromatic heterocyclic ringcomprising one heteroatom selected from N, O or S; R¹ is selected fromhydrogen; halogen; C₁-C₃alkyl; haloC₁-C₃alkyl; hydroxyC₁-C₃alkyl;C₃-C₆cycloalkyl; CH₂NR²R³; CH(CH₃)NR²R³; C₁-C₃alkoxyC₁-C₃alkyl; CH₂CO₂H;C(O)H; C₁-C₃alkoxy; a 5- or 6-membered saturated heterocyclic oraromatic heterocyclic ring comprising at least one heteroatom selectedfrom N, O or S, which ring is optionally substituted once or more thanonce with a group independently selected from C₁-C₃alkyl,haloC₁-C₃alkyl, oxetanyl or oxo; R² is selected from C₁-C₃alkyl,di(C₁-C₃alkyl)aminoC₁-C₃alkyl; R³ is selected from C₁-C₃alkyl,C(O)C₁-C₃alkyl, C(O)—CH₂—OH, C(O)—CH₂—O—CH₃, C(O)—CH₂—N(CH₃)₂, S(O)₂CH₃;or R² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, N-oxide, O or S, which ring may besubstituted once or more than once with R⁴; R⁴ is independently selectedfrom C₁-C₃alkyl, di(C₁-C₃alkyl)amino, C(O)CH₃, hydroxy; or two R⁴attached at the same carbon atom form together with the carbon atom towhich they are attached a 4-, 5- or 6-membered non-aromatic heterocyclicring comprising at least one heteroatom selected from N, O or S; or twoR⁴ attached at the same ring atom form an oxo group; R⁵ is selected fromhydrogen or C₁-C₃alkyl,
 8. A method according to claim 1, wherein thecompound is of formula (Ia-1) or a pharmaceutically acceptable saltthereof


9. A method according to claim 1 wherein said compound is selected fromN-(5-cyanopyridin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;N-(5-cyanopyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;(R)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;(S)—N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-(difluoromethyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;N-(5-cyanopyridin-2-yl)-7-formyl-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;N-(5-cyano-4-isopropoxypyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide;or(R)—N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide.10. A method of treating solid malignancies characterized by positiveFGFR4 and KLB expression, or by positive FGFR4 and FGF19 expression, orby positive FGFR4, KLB and FGF19 expression pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof and one or more pharmaceutically acceptable carriers

wherein V is selected from CH₂, O, CH(OH); W is selected from CH₂,CH₂CH₂, bond; X is C(R^(X)) or N; Y is C(R^(Y)) or N; Z is CH or N;wherein when X is N, Y and Z are not N; wherein when Y is N, X and Z arenot N; wherein when Z is N, X and Y are not N; R^(X) is selected fromhydrogen, halogen, haloC₁-C₃alkyl, cyano, C₁-C₆alkyl, hydroxyC₁-C₆alkyl;R^(Y) is selected from hydrogen, halogen, C₁-C₃alkyl, C₁-C₆alkoxy,hydroxyC₁-C₃alkoxy, NR^(Y1)R^(Y2), cyano, C₁-C₃alkoxyC₁-C₃alkoxy,C₁-C₃alkoxy-haloC₁-C₃alkoxy, di(C₁-C₃alkyl)aminoC₁-C₆alkoxy,O—(CH₂)₀₋₁—R^(Y3), CR^(Y6)R^(Y7), S—C₁-C₃alkyl, haloC₁-C₆alkoxyoptionally substituted with hydroxy; or R^(X) and R^(Y) together withthe ring to which they are attached form a bicyclic aromatic ring systemoptionally further comprising one or two heteroatoms selected from N, O,or S, which ring system is optionally substituted with C₁-C₃alkyl;R^(Y1) is hydrogen and R^(Y2) is C₁-C₆alkyl; hydroxyC₁-C₆alkyl;haloC₁-C₆alkyl optionally substituted with hydroxy;C₁-C₄alkoxyC₁-C₆alkyl; haloC₁-C₃alkoxyC₁-C₆alkyl; (CH₂)₀₋₁—R^(Y4);di(C₁-C₃alkyl)aminoC₁-C₆alkyl substituted with hydroxy;bicyclo[2.2.1]heptanyl substituted with hydroxyC₁-C₃alkyl; phenylsubstituted with S(O)₂—CH(CH₃)₂; bicycloC₅-C₈alkyl; C₂-C₃alkylsulfonicacid; or R^(Y1) and R^(Y2) together with the N atom to which they areattached form a saturated or unsaturated non-aromatic 6-memberedheterocyclic ring which may contain an O atom, which ring may besubstituted once or twice by R^(Y5); R^(Y3) is selected fromquinuclidinyl, a 4-, 5- or 6-membered saturated heterocyclic ringcomprising at least one heteroatom selected from N, O or S, or a 5- or6-membered aromatic heterocyclic ring, which saturated or aromaticheterocyclic ring is optionally substituted with C₁-C₃alkyl and/or oxo;R^(Y4) is a 4-, 5- or 6-membered saturated heterocyclic ring comprisingat least one heteroatom selected from N, O, or S, which ring isoptionally substituted with C₁-C₃alkyl; R^(Y5) is independently selectedfrom C₁-C₃alkyl, hydroxy, di(C₁-C₃alkyl)aminoC₁-C₃alkyl, or two R^(Y5)attached at the same carbon atom form together with the carbon atom towhich they are attached a 5-membered saturated heterocyclic ringcomprising at least one heteroatom selected from N, O or S, which ringis substituted once or more than once with C₁-C₃alkyl; R^(Y6) and R^(Y7)together with the carbon atom to which they are attached form a6-membered saturated or unsaturated non-aromatic heterocyclic ringcomprising one heteroatom selected from N, O or S; R¹ is selected fromhydrogen; halogen; C₁-C₃alkyl; haloC₁-C₃alkyl; hydroxyC₁-C₃alkyl;C₃-C₆cycloalkyl; CH₂NR²R³; CH(CH₃)NR²R³; C₁-C₃alkoxyC₁-C₃alkyl; CH₂CO₂H;C(O)H; C₁-C₃alkoxy; a 5- or 6-membered saturated heterocyclic oraromatic heterocyclic ring comprising at least one heteroatom selectedfrom N, O or S, which ring is optionally substituted once or more thanonce with a group independently selected from C₁-C₃alkyl,haloC₁-C₃alkyl, oxetanyl or oxo; R² is selected from C₁-C₃alkyl,di(C₁-C₃alkyl)aminoC₁-C₃alkyl; R³ is selected from C₁-C₃alkyl,C(O)C₁-C₃alkyl, C(O)—CH₂—OH, C(O)—CH₂—O—CH₃, C(O)—CH₂—N(CH₃)₂, S(O)₂CH₃;or R² and R³ together with the N atom to which they are attached form asaturated 5- or 6-membered ring optionally comprising one additionalheteroatom selected from N, N-oxide, O or S, which ring may besubstituted once or more than once with R⁴; R⁴ is independently selectedfrom C₁-C₃alkyl, di(C₁-C₃alkyl)amino, C(O)CH₃, hydroxy; or two R⁴attached at the same carbon atom form together with the carbon atom towhich they are attached a 4-, 5- or 6-membered non-aromatic heterocyclicring comprising at least one heteroatom selected from N, O or S; or twoR⁴ attached at the same ring atom form an oxo group; R⁵ is selected fromhydrogen or C₁-C₃alkyl.